WO2008129270A2

WO2008129270A2 - Compositions comprising anti-inflammatory compounds

Info

Publication number: WO2008129270A2
Application number: PCT/GB2008/001373
Authority: WO
Inventors: Robert Damms; Humphery-Smith Ian
Original assignee: Renaissance Pharma Ltd; Biosystems Informatics Institute
Priority date: 2007-04-18
Filing date: 2008-04-18
Publication date: 2008-10-30
Also published as: GB0707489D0; WO2008129270A3

Abstract

The present invention provides compositions for providing an effective therapeutic effect at lower drug dosages. A composition of the invention comprises a first formulation of a non-steroidal anti-inflammatory compound (NSAID) and a second formulation of the same NSAID, wherein the dosage amount of the NSAID in the first formulation is higher than that of the second formulation, and wherein the second formulation is a pulsed release formulation which, on administration of the composition, releases the NSAID at a time interval of greater than 12 minutes after the release of the NSAID of the first formulation.

Description

Anti-Inflammatory Compounds Field of the Invention

This invention relates to compositions to reduce inflammatory conditions in a patient and to treat pain. Background to the Invention

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, anti-pyretic and anti-inflammatory effects, ie. they are used to treat pain, fever and inflammation. NSAIDs are particularly suitable for the treatment of pain in its many forms, including musculoskeletal conditions, and to treat headaches.

NSAIDs can be broadly classified based on their chemical structure, and include salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, pyrazolidone derivatives, pyrazolidine, oxicams, coxibs and sulphonanilides.

Of particular therapeutic interest are the salicylates, of which aspirin [2- (acetyloxy)benzoic acid (CAS No. 50-78-2)] is the most well-known example.

Aspirin works by suppressing the production of prostaglandins and thromboxanes due to non-competitive and irreversible inhibition of the cyclooxygenase (COX) enzyme. Aspirin therefore blocks the transmission of pain and inflammation caused by the production of prostoglandins. As thromboxanes are responsible for the aggregation of platelets that form blood clots, aspirin has also been used increasingly for its anti-platelet properties, to reduce the instance of heart attacks.

Aspirin is usually administered in dosage amounts of 30mg-900mg every 4- 6 hours, with a maximum daily dose of up to 4g. However, when used as an anticoagulant (anti-platelet), aspirin is usually administered in oral dosage amounts of 75-81 mg. The latter dosing range is known colloquially as 'baby' aspirin.

One possible undesirable side-effect with long-term use of aspirin is gastric irritation. High doses of aspirin also give rise to gastric irritation, including gastric bleeding and ulcers or exacerbation of pre-existing ulcers, and therefore alternatives to alleviate this have been sought. Summary of the Invention

The present invention is based on the realisation that lower effective doses of NSAIDs, in particular aspirin, can be achieved by the co-administration of two formulations of a NSAID, with one of the formulations having a pulsed-release profile, releasing the NSAID at a time interval of greater than 12 minutes after the release of the first NSAID. In addition, it has been realised by the present inventors that formulating aspirin with aspirin and certain other NSAIDs leads to improvements in the efficacy of NSAIDs, specifically increasing the potency of aspirin at lower doses. This allows lower doses to be administered, which therefore reduces the risk of gastric irritation with conventional doses or equivalent does with higher efficacy. It has also been realised that formulating aspirin with certain other compounds leads to improvements in the efficacy of aspirin, thereby increasing the potency of aspirin at lower doses. The present invention provides novel therapeutic compositions of NSAIDs optionally with co-administration of other compounds, producing favourable changes to the efficacy of the NSAID, allowing reduced dosages to be given.

According to a first aspect of the invention, a composition comprises a first formulation of a non-steroidal anti-inflammatory compound (NSAID) and a second formulation of the same NSAID, wherein the dosage amount of the NSAID in the first formulation is higher than that of the second formulation, and wherein the second formulation is a pulsed-release formulation which, on administration of the composition, releases the NSAID at a time interval of greater than 12 minutes after the release of the NSAID of the first formulation. According to a second aspect of the present invention, a composition comprises aspirin and a different non-steroidal anti-inflammatory compound wherein the aspirin is in a pulsed-release formulation, for delivery before and/or after the different NSAID. In the preferred embodiment, the aspirin is delivered both before and after the different NSAID. According to a third aspect of the present invention, a composition comprises aspirin and a different non-steroidal anti-inflammatory compound, wherein the aspirin is in a pulsed-release formulation, for delivery before or after the different NSAID.

According to a fourth aspect of the present invention, a composition comprises aspirin and an anti-oxidant plant extract.

According to a fifth aspect of the present invention, a composition comprises aspirin and vitamin C and/or a proanthocyanidin, wherein the aspirin is a pulsed- release formulation for delivery before and/or after the vitamin C and/or proanthocyanidin.

According to a sixth aspect of the present invention, a composition comprises aspirin and an anti-oxidant and an anti-fever compound. According to a seventh aspect of the present invention, a composition comprises aspirin and an opiate, morphinomimetic, or a cannabinoid.

According to an eighth aspect of the present invention, there is a pharmaceutical product comprising, in separate unit dosages, a composition as defined above and, either separately or together, an additional compound for co- or sequential administration.

Brief Description of the Figures

The invention is described with reference to the accompanying drawings, wherein:

Figure 1 is a graph showing the concentration (μM) of aspirin in arterial plasma after once a day 75mg administration; and

Figure 2 is a graph showing the plasma administration of (a) proton pump inhibitor, (b) aspirin, (c) an NSAID, (d) low dose aspirin, where ▲ indicates the time of pulsed release of each compound. Description of the Invention The present invention is based, at least in part, on the realisation that the effective dose of a NSAID can be reduced by providing the NSAID in two coadministered formulations; the first being a conventional formulation providing rapid release of the NSAID, and the second formulation being in a pulsed-release form, which releases the NSAID at a time interval greater than 12 minutes after the release of the NSAID of the first formulation. The NSAID of the first formulation will be present in a dosage amount greater than that of the second formulation. Administering the NSAID in this way allows a dose equilibrium to be achieved at a dosage amount lower than that achieved if the sum of the two doses is administered together. The reason for this is that the NSAID of the first formulation will be absorbed rapidly into the blood stream achieving a peak dose over a short time frame. Conventional administration is subject to a rapid peak and then decrease in plasma levels of the NSAID over time, with a consequent decrease in effectiveness of the treatment. The present invention provides a "follow up" dose which can compensate for the decrease in the NSAID plasma level, providing equilibrium to be achieved with lower individual dosing.

Typically, the amount of NSAID, in the case of aspirin, present in the first formulation will be 60mg to 350mg, preferably from 75mg to 81 mg, and present in the second formulation will be 30mg to 150mg, preferably 40mg to 50mg.

The present invention may be carried out with any NSAID, but is particularly suited to the salicylates, in particular aspirin. Suitable salicylates include aspirin, amoxiprin, benorilate, choline magnesium salicylate, diflunisal, faislamine, methyl salicylate, magnesium salicylate and salicyl salicylate. The invention is carried out by providing a first formulation of a NSAID at a higher dose than that of a second formulation of the NSAID, where the second formulation is in a pulsed-release form. As described in more detail below, the invention may be carried out by providing a single composition comprising both formulations in a single unit dosage form, or providing a pharmaceutical pack wherein the first and second formulations are provided separately, but for simultaneous or sequential administration.

The intention of the invention is to deliver to a patient an effective treatment for pain, with reduced potential side effects. This is achieved by administering first and second formulations, where the second formulation is released/administered at a time after the first formulation to provide a therapeutic benefit. The release of the second formulation is said to be "pulsed". This term is intended to mean that the active agent of the second formulation is only delivered/released after a period of time after delivery/release of the active agent of the first formulation. This is not the same as delayed-release, where two therapeutics are released at the same time but at differing delivery rates. Usually, the pulsed release will deliver the active agent of the second formulation after the plasma concentration of the first formulation has returned to an essentially baseline level, as illustrated in Figure 1 , but necessarily after 95% of the compound has been metabolised, for example, as shown in the Area Under Curve in plasma in Figure 1. Without wishing to be bound by theory, the present invention is beneficial as: i) The dose(s) administered at any one instant (but delivered in the same formulation/capsule) enhances compliance and simplifies disease management, thereby reducing the risk of Adverse Drug Effects due to non-compliance. The latter can be of paramount importance in patients at high risk of cardiac arrest, for example. ii) When aspirin, for example, is administered in advance of another NSAID given at a higher therapeutic dose , the prior administration of low dose aspirin enhances the COX-2 selectivity of any given NSAID. All NSAIDs bind to varying degrees to both COX-1 and COX-2. By irreversibly blocking some or all of the available COX-1 , aspirin can, as a consequence, increase the proportion of the therapeutic NSAID directed to COX-2 in a more specific manner, by default, i.e. there is less to bind non-specifically. If aspirin and the therapeutic NSAID are given together they impede one another through competition for both COX-1 and COX-

2 and directly interfere with one another. Thus the solution is not simultaneous delivery, but rather ordered chrono-therapy in conjunction with a variety of combination therapies, including simply aspirin with itself as a better low-dose aspirin for reasons stated below, iii) There is reduced inhibition between the different NSAIDs, and this is especially important when aspirin is to be given in combination with another NSAID for its anti-coagulation / anti-platelet activity. In a preferred embodiment, the first and second NSAID are both aspirin.

The second dose of aspirin is preferably delivered at a period of 3-5 hours after administration of the first dose of aspirin. The provision of a first and second aspirin dose is beneficial as: i) It combats aspirin insensitivity in hyperglycaemic and some other patients; where 'baby' aspirin at 75mg or 81 mg per day is known to represent an insufficient protective dose. ii) It results in an increased area under the curve (AUC) in two peaks in a- once-a-day 75mg or 81 mg dose followed by 40-50 mg dose contained within the same capsule (see Figure One) allowing for a higher dose per day (or per administration, if dual dose aspirin is given more than once per day). As the first dose of Aspirin can be given at below established risk thresholds, it is unlikely to exacerbate gastro-intestinal adverse drug effects. iii) Platelet recruitment over a 24-hour period means that a new population of platelets is not being irreversibly inhibited by anti-platelet aspirin. Thus, so as to reduce the likelihood of thrombotic events in blood, particularly in at-risk patients, the invention can deliver enhanced anti- platelet activity of anti-platlet aspirin in the absence of enhanced risk, i.e. always staying below levels attained by baby aspirin at 75 mg or 81 mg per day. The formulation of the invention is effectively delivering a higher dose, but without surpassing known safety limits of a single dose delivery of drug, via the pulsed- release of the therapeutic. The second formulation is provided to release the NSAID at a time interval of greater than 12 minutes after the release of the NSAID of the first formulation, calculated on the basis of a simultaneous administered dose, but preferably at a lower dose some 1-5 hours, more preferably 3-5 hours after the release of the NSAID of the first formulation. Here, the upper limit for the timing of the pulsed release of the second aspirin dose is determined by the gut passage time, i.e. the upper limit for second dose aspirin administration must fall below the time for orally- administered material (food or drugs) to be passed out in faeces. Pulsed-release formulations are known in the art and conventional chemistries can be used to provide the pulsed-release NSAID formulation, as described in more detail below. Ideally, the active agents (Active Pharmaceutical Ingredients) are to be delivered in a single capsule containing both free APIs and tablet APIs surrounded by varying thickness of coating to facilitate pulsed release. Such a capsule should also desirably keep APIs separate by way of membranes or physical barriers so as to afford healthy shelf-life and prevent APIs from reacting with one another prior to administration to a patient. In this manner up to 4-5 distinct ingredients can be administered in a single capsule containing pure APIs, preformulated combinations of APIs and tablet formations of API linked to pulsed-release of APIs in an ordered manner.

The timing of the release of the second formulation may be influenced by the normal gut passage time in humans of 5-7 hours in healthy adults. During bouts of diarrhoea and other gastro-intestinal disorders, this will be reduced.

Similarly, children have a reduced gut passage time. Accordingly, the time release of the second formulation may need to be varied between different patients. It has also been found by the present inventors that co-administration of a composition according to the invention together with one or more additional compounds can further enhance the safety and / or dose efficacy of the NSAID, resulting in an increased potency at a lower dosage level or higher efficacy at a similar dose or both depending upon the compound doses employed, the combination of compounds and the scheduling of the compounds employed. Accordingly, in further embodiments of the invention, the composition comprising the first and second formulations of the NSAID are used in selected combination with additional compounds. The individual combinations of additional compound(s) for use with the NSAID composition are shown in Table 1. Table 1 Additional compound combinations

1. Different non-steroidal anti-inflammatory compound.

2. One or more of: protein-pump inhibitor, analgesic compound, steroidal anti- inflammatory compound or anti-histamine.

3. Different NSAID and proton-pump inhibitor.

4. Different NSAID; proton-pump inhibitor and a compound selected from the group consisting of: paracetamol; a proanthocyanidin; vitamin C; an anti-oxidant; and an anti-oxidant plant extract. 5. Different NSAID and an anti-fever compound.

6. Anti-oxidant plant extract.

7. Anti-oxidant plant extract and paracetamol/tylenol.

8. Paracetamol (acetaminophen).

9. Paracetamol and a compound selected from the group consisting of: vitamin C; a proanthocyanidin; and an anti-oxidant.

10. Opiates, morphinomimetics, including methylmorphine (codeine) or cannabinoids.

In a preferred composition, the NSAID of the first and second formulations is delivered with a different NSAID, where the different NSAID is delivered after the first formulation but before the second formulation. In a further preferred combination, the composition comprises dual dose aspirin (as the NSAID of the first and second formulations) and naproxen as a different NSAID. In a separate aspect of the invention, it has been found that the administration of aspirin together with the combination of compound(s) shown in Table 1 also provides enhanced potency of aspirin, and / or other NSAIDs, and consequently allows reduced dosage amounts or increased efficacy of the accompanying NSAIDs to be given. Concomitantly, this also allows coadministration of other compounds to address known cardio-vascular and gastrointestinal side-effects and / or enhanced anti-fever and anti-pain action of the associated combination chrono-therapies. Therefore, a conventional aspirin formulation can be provided in combination with any of the compound combinations

10 shown in Table 1.

A skilled person will appreciate which known compounds may be used for each of the broad compound classes specified in Table 1. The following is a non- exhaustive list of each compound class. Non-steroidal anti-inflammatory compounds

15 Proton-pump inhibitors

Omeprazole (Losec®, Prilosec®, Zegerid®) Lansoprazole (Prevacid®, Zoton®, Inhibitol®) Esomeprazole (Nexium®) Pantoprazole (Protonix®, Somac®, Pantoloc®)

Rabeprazole (Rabecid®, Aciphex®, Pariet®) Anti -oxidants

Antioxidants include molecules such as glutathione, vitamin C and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases.

An anti-oxidant is desirable in the combination therapy, as it will have an effect on the target cyclooxygenase, reducing the oxidated state, and thereby reducing the quantity of NSAID (aspirin) likely to achieve a given IC₅₀. This phenomenon is linked to Tyrosine³⁸⁵ having a key role in the natural breakdown (catalytic) of cyclooxygenase and peroxidase activity of the dual enzyme target of all known NSAIDs. Less free oxygen radicals will translate to a lower occurrence of the Tyrosine³⁸⁵ radical and thereby, via a variety of potential mechanisms lead to higher efficacy of aspirin and other NSAIDs towards inhibiting the target. Acetaminophen (paracetamol) Paracetamol (N-(4-hydroxyphenyl)ethanamide) is a common analgesic and anti-pyretic drug, but also possessing antioxidant properties.

The compound is thought by some authors to bind to the peroxidise target and can justifiably be included as a desirable element in the chrono-therapy of the present invention. It has anti-oxidant properties and can act as interim pain-relief while patients await the pulsed delivery of the therapeutic NSAID. It has been suggested that like other phenolic compounds, acetaminophen can act as a reducing agent and quench a tyrosol radical necessary for propagation of the cyclooxygenase reaction (Ouellet, M & Percival MD (2001) Arch. Biochem.

Biophysics. 387: 273-280) and/or specifically contribute to the cyclooxygenase catalytic cycle (natural breakdown of enzymatic activity also the desired endpoint of

NSAID administration). Anti-oxidant plant extracts

Plant-derived antioxidants can be derived from an endless multitude of food and plant substances, but here are protected in combination with aspirin and / or dual dose aspirin in a single formulation delivered as a chronotherapy. Suitable anti-oxidant plant extracts include:

Oxalic acid;

Proanthocyanidins;

Phytic acid;

Tannins; Vitamin C; Ascorbic acid;

Vitamin E; tocopherols, tocotrienols;

Polyphenols antioxidants, resveratrol, flavonoids and caratenoids. Analgesic compound Opiate morphinomimetic, including methylmorphine

(codeine) cannabinoid

Steroidal anti-inflammatory compound

Common natural hormones include corticosterone (C_2IH₃₀O₄), cortisone (C₂₁H₂₈O₅, 17-hydroxy-i i-dehydrocorticosterone) and aldosterone. Anti-histamine ^-receptor antagonists, also known as ^-antihistamines. This class of drug is effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic acetylcholine receptor-antagonists (anticholinergic) agents as well. These agents also commonly have action at α-adrenergic receptors and/or 5- HT receptors. Examples of first generation Anti-histamines include: piperoxan; Ethylenediamines such as, mepyramine (pyrilamine), antazoline; diphenhydramines , such as, carbinoxamine, doxylamine, clemastine, dimenhydrinate; Alkylamines, such as, pheniramine, chlorphenamine (chlorpheniramine), dexchlorphenamine, brompheniramine, triprolidine; Piperazines, such as, cyclizine, chlorcyclizine, hydroxyzine, meclizine; Tricyclics, such as, promethazine, alimemazine (trimeprazine), cyproheptadine, azatadine, ketotifen.

Examples of second generation Antihistamines include: acrivastine, astemizole, cetirizine, loratadine, mizolastine, terfenadine

Examples of third generation Anti-histamines include: levocetirizine, desloratadine, fexofenadine. Other mast cells stabilisers also act as inhibitors of histamine release and include: cromoglicate (cromolyn), nedocromil

H₂-receptor antagonists include: cimetidine, ranitidine, and famotidine.

H₃- and H₄-receptor antagonists include: ABT-239, Thioperamide, Clobenpropit, lmpromidine and Thioperamide Anti-fever compounds

Commonly used anti-fever treatments include, NSAIDs and acetaminophen.

Proanthocyanidins

Proanthocyanidins are a class of flavinoids which have anti-oxidant properties, and which are derived from grape seed extract. Table 2 provides the preferred, minimum and maximum dosage amounts of the medicinal compounds to be used in a combination with either the NSAID composition or aspirin, according to the invention and the delivery of proton pump inhibitors to reduce gastro-intestinal side effects, all as part o a combination chronotherapy. In a preferred embodiment, the NSAID (eg. aspirin) of the first and second formulations are released after release of the additional compound. In a particularly preferred embodiment, a proton pump inhibitor is administered before the aspirin or NSAID. Table 2

Dosage (mg/day)

Minimum Maximum Preferred

1. Aspirin first formulation 60mg 350mg 75mg

2. Asprin Second formulation 30mg 150mg 45mg

3. Naproxen, an example NSAID 200mg 650mg 450mg

4. Omeprazole, Proton-pump inhibitor, 5mg 70mg 25mg

Noting that quite often the final dosage will be dictated by the space available within a given capsule and whether such formulations are to be administered once daily or more often in association with patients suffering from to mild to moderate chronic pain or severe chronic pain or acute pain, for example, and the inherent likelihood of the occurrence of 'pain breakthrough' and the need treat such being complicated by the slow onset of the therapeutic dose of NSAID in a particular combination chronotherapy.

The compounds disclosed herein may be used in their free base form or as a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts include, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2-(4- hydroxybenzoyl)benzoic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p- toluenesulphonic acid, 10-undecenoic acid and the like. The most preferred salts are those of hydrochloric acid. It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy in accordance with the present invention. Such salts may be prepared by conventional chemistries.

The compounds for use in the invention may also be prepared by any suitable method known in the art. Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances. In therapeutic use, the active compound may be administered orally, rectally, parenterally or by inhalation (pulmonary delivery). Oral administration is preferred. When the NSAID or aspirin is to be used in combination with another compound as specified herein, the compounds may be incorporated as separate dosage forms or may be formulated into a single dosage form. Whether formulated as separate or combined dosage forms, the intention is to facilitate coadministration, ie. the compounds are to be administered at the same time, either simultaneously or sequentially. Thus, a single dosage form can be formulated for simultaneous release of the actives by any formulation technique conventionally known in the art, while separate dosage forms may be administered according to a sequential, ie. staggered, dosage regimen.

Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The medicaments used in the invention may contain about 0.1 to about 99% by weight of active compound and typically contain proportions of active formulated in accordance with standardised active levels for different patient types and/or different strengths of medicament depending upon the desired dosage regimen, for example. The medicaments are generally prepared in unit dosage form. Preferably, a unit dose comprises the one or more active ingredients in an amount of about 0.1 to about 500 mg, more preferably about 20 to about 350mg, even more preferably about 30 to about 200mg, and most preferably 30-40mg. Excipients used in the preparation of these medicaments may be standard excipients known in the art for this purpose.

Although guidance is given in Table 2, appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, p450 allelic variation, obesity, cardiac risk profile, drug combination and the severity of the disease undergoing treatment. For example, for an adult patient being administered aspirin, a typical dosage is about 2g/kg daily.

Medicaments for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets are preferred. Medicaments intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such medicaments may contain one or more agents in order to provide pharmaceutically elegant and palatable preparations. Such suitable agents include sweetening agents, flavouring agents, colouring agents or preserving agents. Tablets contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated.

The second formulation of NSAID (eg. aspirin) is in a pulsed-release formulation. This may be achieved by techniques known to delay disintegration and absorption of the drug(s) in the patient. A time-delay material such as glyceryl monostearate or glyceryl distearate may be employed for this purpose.

Ideally, the first and second formulations are delivered in a single capsule containing both free active agents and tablet active agents surrounded by varying thickness of coating to facilitate pulsed release. Such a capsule would also desirably keep the actives separate by way of membranes or physical barriers so as to afford healthy shelf life and prevent the actives from reacting with one another prior to administration to a patient. In this manner up to 4-5 distinct ingredients could be administered in a single capsule containing pure active agents, preformulated combinations of active agents and tablet formations of active agent linked to pulsed release of active agents in an ordered manner.

Formulations for oral use may also be presented as hard capsules, preferably gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. Alternatively, soft, preferably gelatin, capsules, in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil, may be provided. The medicaments used in the present invention may also be in the form of aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Suitable excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more additional agents such as preservatives, for example ethyl or n-propyl p-hydroxybenzoate; colouring agents; flavouring agents; and sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in a mineral oil such as liquid paraffin or in other surfactants or detergents. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water typically provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Again, suitable sweetening, flavouring and colouring agents may also be present.

The medicaments used in the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Again, the emulsions may contain additional agents such as sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example

, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The medicaments may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any conventionally known bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectable medicaments.

Conveniently, the medicament used according to the present invention, whether comprising the NSAID formulations alone or in combination with other drug actives, as disclosed herein, is provided in the form of a kit comprising the medicament and instructions that the medicament is to be used for the treatment of pain (analgeisa), inflammation or, in the context of aspirin, to reduce platelet aggregation. If the medicament comprises the NSAID or aspirin composition and one or more additional drug actives in separate dosage forms, the instructions provide details of the dosage regimen to be employed.

The compositions etc of the invention are to be used in the treatment of conditions which are treated typically with conventional aspirin or NSAIDs. For example, the compositions are for use in treating inflammatory disorders, pain and fever. The compositions may also be used to prevent or retard platelet aggregation, thereby reducing the risk of cardiac arrest in at-risk patients, such risk being sometimes exacerbated by Cox-2 inhibiting NSAIDs themselves. The compositions of the invention are therefore useful in the manufacture of a medicament for the treatment of inflammation, pain (analgesia) or fever.

Claims

U18Claims

1. A composition comprising a first formulation of a non-steroidal antiinflammatory compound (NSAID) and a second formulation of the same NSAID, wherein the dosage amount of the NSAID in the first formulation is higher than that 5 of the second formulation, and wherein the second formulation is a pulsed release formulation which, on administration of the composition, releases the NSAID at a time interval of greater than 12 minutes after the release of the NSAID of the first formulation.

10 2. A composition according to claim 1 , wherein the NSAID in the first and second formulation is aspirin.

3. A composition according to claim 1 or claim 2, further comprising a different non-steroidal anti-inflammatory compound.

15

4. A composition according to claim 3, wherein the different NSAID is delivered after the first aspirin dose but before the second aspirin dose.

5. A composition according to claim 3 or claim 4, further comprising a proton- 20 pump inhibitor, a steroidal anti-inflammatory compound, an additional analgesic compound or an anti-histamine compound.

6. A composition according to claim 5, further comprising a compound selected from the group consisting of:

25 proanthocyanidin; vitamin C; an anti-oxidant; and an anti-oxidant plant extract.

7. A composition according to claim 3 or claim 4, further comprising an anti- fever compound.

30

8. A composition according to claim 1 or claim 2, further comprising an antioxidant plant extract.

9. A composition according to claim 8, further comprising acetaminophen (paracetamol).

10. A composition according to claim 1 , further comprising acetaminophen (paracetamol).

11. A composition according to claim 10, further comprising a compound selected from the group consisting of: vitamin C; a proanthocyanidin; and an anti-oxidant.

12. A composition according to claim 11, further comprising an anti-fever compound.

13. A composition according to claim 1 or claim 2, further comprising vitamin C and/or a proanthocyanidin.

14. A composition according to claim 13, further comprising an anti-fever compound.

15. A composition according to claim 1 or claim 2, further comprising an anti- oxidant and an anti-fever compound.

16. A composition according to claim 1 or claim 2, further comprising an opiate, morphinomimetic, or a cannabinoid compound.

17. A composition according to any of claims 3 and 5 to 16, wherein the aspirin or NSAIDs of the first and second formulation is released after release of the additional compound(s).

18. A pharmaceutical pack, comprising, in separate unit dosages, a composition of claim 1 or claim 2 and, either separately or together, the additional compound(s) as defined in any of claims 3 to 16.

19. A composition comprising aspirin and a different non-steroidal antiinflammatory compound, wherein the aspirin is in a pulsed-release formulation, for delivery before or after the different non-steroidal anti-inflammatory compound.

20. A composition according to claim 19, further comprising a proton-pump inhibitor, a steroidal anti-inflammatory compound, an additional analgesic compound or an anti-histamine compound.

21. A composition according to claim 20, further comprising a compound selected from the group consisting of: paracetamol (tylenol); a proanthocyanidin; vitamin C; an anti-oxidant; and an anti-oxidant plant extract.

22. A composition according to claim 19, further comprising an anti-fever compound.

23. A composition according to claim 19, further comprising an opiate, morphinomimetic or cannabinoid compound.

24. A composition comprising aspirin and an anti-oxidant plant extract.

25. A composition according to claim 24, further comprising acetaminophen (paracetamol).

26. A composition according to claim 25, further comprising a compound selected from the group consisting of: vitamin C; a proanthocyanidin; and an anti-oxidant.

27. A composition according to claim 26, further comprising an anti-fever compound.

28. A composition according to any of claims 25 to 27, wherein the further compound is in a form for delivery before delivery of the aspirin.

29. A composition comprising aspirin and vitamin C and/or a proanthocyanidin, wherein the aspirin is in a pulsed-release formulation for delivery before and/or after the vitamin C and/or proanthocyanidin.

30. A composition according to claim 29, wherein the aspirin is delivered both before and after the vitamin C and/or proanthocyanidin.

31. A composition according to claim 29 or claim 30, further comprising an anti- fever compound.

32. A composition according to claim 19, further comprising an opiate, morphinomimetic or cannabinoid compound.

33. A composition comprising aspirin and an anti-oxidant and an anti-fever compound.

34. A composition according to any of claims 31 to 33, wherein the further compound(s) is in a form for delivery before delivery of the aspirin.

35. A pharmaceutical pack comprising, in separate unit dosages, a composition comprising aspirin and, either separately or together, the additional compound(s) as defined in any of claims 19 to 22, in the stated combinations.

36. A pharmaceutical pack comprising, in separate unit dosages, a composition comprising aspirin and an anti-oxidant plant extract, and optionally the additional compounds defined in claims 25 to 27.

37. A pharmaceutical pack comprising, in separate unit dosages, a composition comprising aspirin and vitamin C and/or a proanthocyanidin.