WO2005021041A1

WO2005021041A1 - Intranasal formulations of meloxicam

Info

Publication number: WO2005021041A1
Application number: PCT/GB2004/003604
Authority: WO
Inventors: Jonathan David Castile; Wu Lin; Alan Smith; Peter James Watts
Original assignee: Archimedes Development Limited
Priority date: 2003-08-30
Filing date: 2004-08-24
Publication date: 2005-03-10
Also published as: GB0320382D0

Abstract

The present invention provides an aqueous composition for nasal administration comprising: (i) from 26 to 120 mg/ml of meloxicam; (ii) a base; and (iii) a solubility enhancing agent. Preferred solubility enhancing agents include poloxamers and polyethylene glycols. Additional solubility enhancing agents such as cyclodextrins and benzyl alcohol may also be used.

Description

LNTRANASAL FORMULATIONS OF MELOXICAM

This invention relates to pharmaceutical compositions for the intranasal administration of the compound meloxicam.

Meloxicam is 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-l,2- benzothiazine-3-carboxamide 1,1 -dioxide (molecular weight 351.4) and has the following structure.

Meloxicam is a non-steroidal antiinflammatory drug (NSAID) that has antiinflammatory, analgesic and antipyretic activity (see Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman et al (eds) pages 640-641, 9^ώ edition, 1996, McGraw-Hill, New York). NSAIDs are inhibitors of the enzyme cyclooxygenase (COX). Two forms of cyclooxygenase are known, COX-1 and COX-2. COX-1 is constiτutively expressed and is responsible for producing homeostatic prostaglandin and thromboxane mediators. COX-2 is produced in response to stimuli such as infection and inflammation.

Inhibition of COX-2 is thought to be the primary route by which NSAIDs exert their therapeutic action. Inhibition of COX-1 is thought to produce some of the adverse effects of NSAIDs, such as gastrointestinal ulceration. Meloxicam has selectivity towards COX-2 and may have an advantageous side-effect profile. Meloxicam can be used in the treatment of pain. More specifically it is used in the management of rheumatoid arthritis, for the short term symptomatic treatment of acute exacerbations of osteoarthritis and for the symptomatic treatment of ankylosing spondylitis. 5 The nasal route of drag delivery affords rapid absorption of drugs into the blood circulation. In some cases absorption of almost the whole dose can be achieved and the pharmacokinetics can be similar to intravenous administration. Such rapid and effective drug delivery can be useful in the 10 treatment of crisis situations such as pain. For a review article on intranasal drug delivery see Ilium, Drug Discovery Today, 7, 1184-1189, 2002.

Oil-in-water emulsion compositions for the intranasal administration of drugs, including NSAIDs such as meloxicam, are described in WO 15 00/24373. Although such compositions are useful for the delivery of poorly water-soluble drugs in a liquid form and may offer improved nasal tolerance of irritant drugs, emulsions are complex systems and present a number of stability and manufacturing challenges.

20 It would, therefore, be desirable to be able to deliver meloxicam intranasally as a homogeneous solution. However, meloxicam has very low aqueous solubility (approximately 0.0005 mg/ml at pH 4 and 1 mg/ml at pH 7.4). This presents problems in producing solution compositions for therapeutic use. An intranasal solution composition for therapeutic use needs to contain

25 an efficacious amount of drug within an acceptable volume of liquid. For example, an intranasal liquid formulation is preferably administered using a spray pump and the typical volume of liquid dispensed is 0.1 ml/spray, although pumps dispensing up to 0.14 ml per spray are available commercially. It is a practical proposition to administer up to around 0.2 ml

3.0 into each nostril (e.g. two x 0.1 ml sprays) to provide a therapeutic dose of drug, although the most acceptable dosing regimen would be one spray into one or both nostrils.

The dose of meloxicam used in the treatment of osteoarthritis and rheumatoid arthritis is from 7.5 to 15 mg and it is assumed that a dose of up to 15 mg will be efficacious in the treatment of pain. On this basis, the meloxicam concentration required in an intranasal solution to be administered in one or two 0.1 ml or 0.14 ml sprays can be estimated as follows:

Although solutions containing meloxicam are described in the prior art, none provide the high concentrations needed for an intranasal dosage form.

For example, Stei et al (Brit. J. Rhematology, 35 (suppl. 1), 44-50, 1996) describes a solution containing 10 mg/ml meloxicam, prepared by dissolving meloxicam in a solution of base (meglumine) with glycofurol and Pluronic F68 (poloxamer 188) added to improve drug stability.

WO 01/97813 describes meloxicam solutions. However, the maximum concentration of meloxicam disclosed is 25 mg/ml. Compositions containing concentrations of meloxicam up to 25 mg/ml are of limited use for intranasal administration.

WO 99/09988 also describes meloxicam solutions. Again, these solutions do not contain meloxicam in an amount that would make them suitable for nasal administration.

The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

We have surprisingly found that aqueous compositions containing a high concentration of meloxicam may be prepared, which are stable, are well tolerated when administered intranasally and provide for rapid and effective systemic drug absorption.

By "well tolerated", we include compositions that cause minimal stinging and itching when applied into the nasal cavity such that a patient is not dissuaded from receiving further doses of the drug.

The present invention provides an aqueous composition for nasal administration comprising: (i) f om 26 to 120 mg/ml of meloxicam; (ii) a base; and (iii) a solubility enhancing agent, which compositions are referred to hereinafter as "the compositions of the invention".

The concentration of meloxicam in the compositions of the invention is from 26 to 120 mg/ml, preferably from 28 to 100 mg/ml, more preferably from 30 to 90 mg/ml, most preferably from 35 to 80 mg/ml, for example from 37 (e.g. 50) to 60 mg/ml.

Both organic and inorganic bases may be used in the compositions of the present invention. However, an organic base is preferably used. Suitable organic bases include, but are not limited to, tromethamine, meglumine (N- methyl-D-glucamine) and lysine. The use of meglumine (molecular weight 195.2) is especially preferred.

The amount of base included in the compositions, expressed as number of moles of base per mole of meloxicam, is preferably from 0.7 to 1.8, more preferably from 0.8 to 1.6 and most preferably from 0.9 to 1.4.

The compositions of the invention comprise a solubility enhancing agent.

By the term "solubility enhancing agent" or "solubility enhancer" we mean a water-soluble ingredient (having a solubility in water of 10 mg/ml or greater) that, in the presence of a mixture of meloxicam and base, in the ratio stated above, is able to increase the amount of meloxicam that can dissolve. Thus, when the meloxicam and base are added to an aqueous solution containing the solubility enhancing ingredient, the amount of meloxicam that will dissolve is higher than when meloxicam and base are added to water only.

Preferably, the solubility enhancing agent is a poloxamer or a polyethylene glycol.

Poloxamers are block copolymers of ethylene oxide and propylene oxide and have the general formula HO(C₂H 0)_a(C₃H6θ)b(C₂H₄θ)_aH, wherein a is from 2 to 130 and b is from 15 to 67. Several different types of poloxamer are available commercially, from suppliers such as BASF, and vary with respect to molecular weight and the proportions of emylene oxide "a" units and propylene oxide "b" units. Examples of commercially available poloxamers suitable for use in the present invention include poloxamer 188, which structurally contains 80 "a" units and 27 "b" units, and has a molecular weight in the range 7680-9510 and poloxamer 407 which structurally contains 101 "a" units and 56 "b" units, and has a molecular weight in the range 9840-14600 (Handbook of Pharmaceutical Excipients, editors R C Rowe, P J Sheskey and P J Weller, 4^th edition, Pharmaceutical Press, London, UK, 2003).

If a composition of the invention comprises a poloxamer, the poloxamer is preferably present at a concentration of from 10 to 350 mg/ml w/v, more preferably from 30 to 300 mg/ml and most preferably from 50 to 250 mg/ml.

Polyethylene glycols (also known as macrogols or PEGs) are liquid and solid polymers of the formula H(OCH₂CH₂)„OH, where n is at least 4. PEGs having a wide range of molecular weights are available commercially and are listed in pharmacopoeias. For example, the US National Formulary lists specifications for PEGs with average molecular weights in the range 200-8000 and the European Pharmacopoeia lists specifications for PEGs with a range of average molecular weights such as 300, 400, 600, 1000, 1500, 3000, 3350, 4000, 6000, 8000, 20000 and 35000. PEGs of molecular weight 600 and below are typically liquid at ambient temperature, while those of molecular weight 1000 and above are solid at ambient temperature.

PEGs repoήedly have low toxicity, although any toxicity appears to be greatest with low molecular weight PEGs. For example, they may cause stinging when applied to mucous membranes (page 1630, Martindale, 33^rd edition, Pharmacuetical Press, London, 2002). In addition, when dissolved in aqueous solution at a given weight, the higher the molecular weight of the PEG, the lower the osmolality of the solution (see, for example, Example 19), which will in tarn minimise irritation. Higher molecular weight PEGs are inherently less irritant to the nasal mucosal membrane and, when dissolved in aqueous solution at a given weight, produce a solution with a lower osmolality, which will in turn minimise irritation. However, as the molecular weight of the PEG increases, its viscosity in aqueous solution will also increase and, if too high, may present problems in producing a nasal composition that can be dispensed using a spray device. Hence, the molecular weight of the PEG preferably needs to be carefully chosen in order to produce a sprayable solution that is well tolerated when administered into the nasal cavity.

The average molecular weight of the PEGs used in the present invention is preferably from 300 to 35000, more preferably from 1000 to 20000 and most preferably from 3000 to 10000. The most preferred PEG has an average molecular weight of 8000. PEG 8000 is commercially available from, for example BASF (Germany) or Dow Chemical Co. (USA).

If the compositions of the present invention contain a PEG, it is preferably present in a concentration of from 10 to 350 mg/ml, more preferably from 30 to 300 mg/ml and most preferably from 50 to 250 mg/ml.

Optionally, the compositions of the invention may contain more than one solubility enhancer. For example, the compositions may comprise polyethylene glycol and/or poloxamer and an additional solubility enhancer. It is especially advantageous for the compositions of the invention to comprise an additional solubility enhancer when the meloxicam concentration is high. This can help prevent precipitation of the drug on long term storage or at low temperatures. By high concentration of meloxicam we mean a concentration of 50 mg/ml or above.

Preferred additional solubility enhancers include, but are not limited to, cyclodextrins and benzyl alcohol.

Cyclodextrins are oligosaccharides made up of glucopyranose units and produced by the enzymatic degradation of starch. They are "bucketlike" or "conelike" toroid molecules with a rigid structure and a central cavity, the size of which varies according to the cyclodextrin type. The internal cavity of cyclodextrins is hydrophobic and may allow for the inclusion of lipophiiic molecules, thus improving the aqueous solubility of poorly soluble drugs (Thompson, Crit. Rev. Ther. Drug Carr. Sys., 14, 1-104, 1997).

The three major types of cyclodextrin (CD) are α, β and y which comprise 6, 7 and 8 glucopyranose units respectively. To extend their usefulness as pharmaceutical excipients, CDs, in particular β-CD, have been chemically modified, for example to produce derivatives that have enhanced aqueous solubility. Such derivatives include but are not limited to carboxymethyl-β- CD, carboxymethyl-ethyl-β-CD, diethyl-β-CD, methyl-β-CD, dimethyl-β- CD, trimethyl-β-CD, randomly methylated β-CD, glucosyl-β-CD, maltosyl- β-CD, hydroxyethyl-β-CD, 2-hydroxyproρyl-β-CD and sulfobutylether-β- CD. The preferred cyclodextrins for use in the present invention are α-CD, β- CD, γ-CD and the modified derivatives of β-CD, such as 2-hydroxypropyl- β-CD, randomly methylated β-CD and sulfobutylether-β-CD. Especially preferred cyclodextrins are γ-CD, 2-hydroxypropyl-β-CD, randomly methylated β-CD and sulfobutylether-β-CD. Suppliers of γ-CD, hydroxypropyl-β-CD and randomly methylated β-CD include ISP (Wayne, NJ, USA), Roquette (Lestrem, France) and Cerestar (Mechelen, Belgium). Sulfobutylether-β-CD can be obtained from CyDex Inc (Overland Park, KS, USA) under the trade name Captisol®.

If the compositions of the invention comprise a CD, the CD is preferably present in an amount of from 10 to 1500 mg/ml, more preferably from 25 to 1000 mg/ml and most preferably from 50 to 500 mg/ml.

Benzyl alcohol is typically used at low concentrations (typically up to 20 μl/ml) in pharmaceutical formulations as an antimicrobial preservative and at higher concentrations (typically 50 μl/ml or greater) as a solubiliser (pages 53-55, Handbook of Pharmaceutical Excipients).

Surprisingly, we have found that the use of low concentrations of benzyl alcohol can substantially improve the aqueous solubility of meloxicam.

If the compositions of the present invention comprise benzyl alcohol, it is preferably present in an amount of from 1 to 50 μl/ml, more preferably from 2.5 to 40 μl/ml and most preferably from 5 to 30 μl/ml.

A preferred composition of the invention comprising a relatively low dose of meloxicam comprises from 26 (e.g. 30) to 49 mg/ml meloxicam; tromethamine, meglumine or lysine as a base; and from 50 to 250 mg/ml of a poloxamer or from 50 to 250 mg/ml of a polyethylene glycol with a molecular weight of from 3000 to 10000. If this composition contains a poloxamer, it preferably contains poloxamer 188 or poloxamer 407.

Poloxamers in aqueous solution have thermogelling properties and become more viscous as the temperature increases (see Yong et ah, Int. J. Pharm., 226, 195-205, 2001). However, this effect is more pronounced with poloxamer 407 and hence this type of poloxamer may be preferred for use in the low dose meloxicam compositions. The increase in viscosity may increase the residence of the formulation in the nasal cavity and thereby improve drug absorption due to the longer contact time with the absorptive tissues.

An especially preferred composition of the invention comprising a relatively low dose of meloxicam comprises from 30 to 40 mg/ml meloxicam, from 16 to 27 mg/ml meglumine and from 100 to 200 mg/ml poloxamer 407 or from 100 to 200 mg/ml PEG 8000.

A preferred composition of the invention comprising a relatively high dose of meloxicam comprises from 50 to 120 mg/ml meloxicam; meglumine or lysine as a base; either from 50 to 250 mg/ml of a poloxamer or from 50 to 250 mg/ml polyethylene glycol and from 5 to 500 mg/ml of a cyclodextrin or from 5 to 30 μl/ml of benzyl alcohol.

A preferred poloxamer for use in compositions containing a relatively high dose of meloxicam is poloxamer 188, since the physical stability of meloxicam appears to be higher in the presence of this type of poloxamer (see Example 18). An especially preferred composition of the invention comprising a relatively high dose of meloxicam comprises from 50 to 60 mg/ml meloxicam, from 27 to 40 mg/ml meglumine, from 40 to 160 mg/ml poloxamer 188 and from 150 to 250 mg/ml HP-β-CD or from 15 to 25 μl/ml benzyl alcohol.

The compositions of the present invention preferably have a pH of from 6.0 to 10.5, more preferably from 7.0 to 10.0 and most preferably from pH 7.5 to 9.5.

In addition to enhancing the aqueous solubility of the meloxicam, poloxamers and PEGs may also provide thickening or in the case of poloxamers thickening and/or gelling properties if included at an appropriate concentration. Alternatively or additionally to the use of a PEG or a poloxamer in a concentration that provides thickening or gelling properties, the compositions of the invention may contain one or more thickening or gelling agents such as celluloses (e.g. hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose and microcrystalline cellulose), xanthan gum, pectin, alginic acid and salts thereof.

The compositions of the invention optionally contain one or more other ingredients such as antioxidants (for example sodium metabisulphite), chelating agents (for example edetic acid (EDTA) or one of. its salts), preservatives (such as benzalkonium chloride, sorbic acid or one of its salts, phenylethyl alcohol and/or propyl hydroxybenzoate), sweeteners (such as saccharin or aspartame), flavours (such as peppermint) and other agents generally used in pharmaceutical liquid preparations and well known to those of skill in the art. Preferably, the compositions of the invention comprise EDTA or a salt thereof. EDTA and its salts are typically used as chelating agents in pharmaceutical fomiulation to enhance stability, prhnarily by acting as antioxidant synergists. They also have some antimicrobial activity. Suitable salts of EDTA include the dipotassium, disodium, calcium disodium, trisodium and tetrasodium salts. If the compositions of the present invention contain EDTA or one of its salts, the concentration of EDTA is preferably from 0.01 to 2.50 mg/ml, more preferably from 0.02 to 2.00 mg/ml and most preferably from 0.05 to 1.50 mg/ml.

The viscosity of the compositions of the present invention is preferably less than 250 centipoise (cp), more preferably less than 200 cp and most preferably less than 150 cp.

The osmolality of the compositions of the invention is preferably from 0.25 to 1.10 osmol/kg, more preferably from 0.25 to 1.05 osmol/kg and most preferably from 0.25 to 1.00 osmol/kg.

Preferably the compositions of the invention contain a preservative and/or are sterile.

Preferably the compositions of the invention are non-pyrogenic.

The water used to prepare the compositions of the present invention is preferably boiled and cooled and/or purged with a gas such as helium in order to minimise the dissolved oxygen content and hence maximise drug stability.

The compositions of the invention may be administered to the nasal cavity in any suitable form, for example in the form of drops or a spray. Methods suitable for administering a composition to the nasal cavity will be well known by the person of ordinary skill in the art. Any suitable method may be used. The preferred method of administration is the use of a spray device. Spray devices can be single (unit) dose or multiple dose systems, for example comprising a bottle, pump and actuator, and are available from various commercial sources including Pfeiffer, Valois, Bespak and Becton- Dickinson. Electrostatic spray devices, such as described in US 5,655,517, are also suitable for the intranasal administration of the compositions of the present invention.

For a spray device, the typical volume of liquid that is dispensed in a single spray actuation is in the range of from 0.01 to 0.14 ml. A typical dosing regimen for a nasal spray product would be in the range of one spray into a single nostril to two sprays into each nostril.

The present invention also provides a spray device or a dose cartridge for use in a nasal delivery device loaded with a composition as defined above. The present invention also provides a process for preparing a composition as described above. This process comprises mixing the components in water. If necessary, the composition can be sonicated to aid dissolution of the components. Purified water such as water for injections may be used in the compositions , of the present invention.

The compositions can be used for the treatment, management or prevention of inflammation and both acute and chronic pain in animals including humans. The compositions of the invention can be used to treat, manage or prevent pain in a wide variety of pain conditions such as those associated with rheumatoid arthritis, acute exacerbations of osteoarthritis and ankylosing spondylitis. Other uses of the compositions include treating or managing the pain associated with conditions such as headache, migraine, neuralgia and dental pain, pain associated with injury and accident trauma and pain following surgery. Thus, the present invention provides a method of administering meloxicam to a patient in need thereof, such as a patient suffering from any of the conditions listed above, which comprises the intranasal administration of a composition as defined above to the patient.

The present invention also provides the use of a base and a solubility enhancing agent in the manufacture of an aqueous composition for nasal administration comprising from 26 to 120 mg/ml of meloxicam which may, for example, be used to treat, manage or prevent the conditions listed above.

The compositions of the present invention have the advantage that they enable the intranasal administration of meloxicam, which is not practical using aqueous compositions containing lower concentrations of meloxicam.

In the figures:

Figure 1 shows plasma concentration profiles following administration of meloxicam to sheep by intravenous and intranasal routes.

The invention is illustrated by the following non-limiting examples. Example 1 - Intranasal solution containing approximately 37.5 mg/ml of meloxicam and 150 mg/ml poloxamer 188

A 1M meglumine solution was prepared by dissolving 9.76 g of meglumine (Sigma, UK) in 35 ml of water and then making the solution up to 50 ml with water. In a 100 ml volumetric flask, 3.75 g of meloxicam (Zhejiang Jingjin Pharmaceutical Chemical Co., China) was dissolved in 11.74 ml of the 1M meglumine solution. 15 g of poloxamer 188 (Sigma) and 30 ml of water were added to the meloxicam solution which was then sonicated (ultrasonic bath, Decon, Hove, UK) to dissolve the poloxamer. 0.5 ml of phenylethyl alcohol (R. C. Treatt, UK) and 20 mg of sodium propylparabens (Nipa Laboratories, Pontypridd, UK) were added to the meloxicam solution as preservatives. The solution was made to volume with water. The pH of the solution was 8.8 and the osmolality was 0.48 osmol/kg.

Example 2 - Intranasal solution containing approximately 75 mg/ml meloxicam, 50 mg/ml poloxamer 188 and 200 mg/ml hydroxypropyl-β- cyclodextrin

A 15 mg/ml solution of benzalkonium chloride solution was prepared by weighing 0.3 g of 50% w/v benzalkonium chloride solution (Albright &

Wilson, UK) into a 10 ml volumetric flask and making up to volume with water. In a 100 ml volumetric flask 7.5 g of meloxicam (Zhejiang Jingjin

Pharmaceutical Chemical Co., China) was dissolved in 23.4 ml of 1M meglumine solution. 5 g of poloxamer 188 (Sigma, UK) was added to the meloxicam solution which was then sonicated to dissolve the poloxamer.

20 g of hydroxypropyl-β-cyclodextrin (HP-β-CD) (Wacker, Germany) and approximately 10 ml of water was added to the meloxicam solution and the cyclodextrin dissolved by sonication. Finally, 1 ml of 15 mg/ml benzalkonium chloride solution was added to the meloxicam solution as a preservative. The solution was made to volume with water. The pH of the solution was 8.6 and the osmolality was 0.88 osmol/kg.

Example 3 - Intravenous solution containing 1 mg/ml meloxicam

A 45 mg/ml mannitol solution was prepared by dissolving 11.25 g of mannitol (Sigma) in 200 ml of water and then making to 250 ml with water. 200 mg of meloxicam and 2 g of PEG 400 (Sigma) were weighed into a 200 ml volumetric flask and 180 ml of the mannitol solution added. The flask contents were sonicated until the meloxicam had dissolved. The flask contents were made to volume with water and 20 ml portions sterile filtered (0.2 μm syringe filters) into sterile injection vials which were sealed with elastomer stoppers and metal caps.

Example 4 - Pharmacokinetic testing in sheep

The pharmacokinetic performance of the intranasal meloxicam solutions described in Examples 1 and 2 was evaluated in the sheep. For purposes of bioavailability calculations, the intravenous injection in Example 3 was administered.

A group of four animals was used. In the first leg of the study the intravenous injection was administered at a dose of 7.5 mg. In legs two and three of the study the two nasal formulations were administered following a randomised cross-over design. Each nasal formulation was administered at a meloxicam dose of 30 mg. This was provided by 0.8 ml of the formulation described in Example 1 and 0.4 ml of the formulation described in Example 3. Nasal doses were administered via a spray device with the dose volume being divided equally between both nostrils. The formulations were well tolerated by the sheep, as measured by the frequency of snorting and sneezing post-dose. Blood samples were collected and plasma separated. Plasma samples were assayed by an HPLC method for meloxicam content. Pharmacokinetic parameters were calculated from the plasma data.

Mean plasma concentration-time curves for the two nasal formulations and the intravenous injection are shown in Figure 1. A summary of pharmacokinetic parameters is provided in Table 1.

Table 1. Mean pharmacokinetic parameters following intranasal administration of meloxicam to sheep by intranasal and infravenous routes

Example 5 - Effect of benzyl alcohol on the physical stability of solutions containing approximately 55 mg/ml meloxicam and 150 røg/mϊ poloxamer 188

275 mg of meloxicam was weighed into each of three 5 ml volumetric flasks. 5 mg EDTA disodium and 750 mg poloxamer 188 was added to each flask. To one of the flasks was added 0.05 ml of benzyl alcohol (Sigma, Poole, UK) and to another was added 0.1 ml of benzyl alcohol. 0.87 ml of 1M meglumine solution and 3 ml of water was then added to each flask, the contents stirred until dissolved and then made up to 5 ml with water. The final solutions were transferred into 5 ml injection vials which were each sealed with a rubber stopper and aluminium cap. The vials were placed into an incubator at 2-8°C and stored for 4 weeks after which they were examined. The appearance of the solutions is noted in Table 2.

Table 2. Effect of benzyl alcohol on meloxicam solubility

The above data indicate that incorporating 20 μl/ml of benzyl alcohol into an approximately 55 mg/ml meloxicam solution prevented drug precipitation when stored at 4°C. This suggests that benzyl alcohol may improve the solubility of meloxicam when stored at low temperatures. Example 6 - Solution containing approximately 37.5 mg/ml meloxicam and 150 mg/ml poloxamer 407 ("Formulation A")

19.52 g of meglumine was weighed into a 100 ml volumetric flask and approximately 80 ml of boiled and cooled water for injections was added. The flask was placed into an ultrasonic bath for 10-15 minutes to dissolve the meglumine and then the contents made up to volume with boiled and cooled water for injections. 1.875 g of meloxicam (Techno, Andhero, India) was weighed into a 50 ml volumetric flask and 5.87 ml of the meglumine solution added. 7.5 g of poloxamer 407 (Sigma), 50 mg of EDTA disodium (Sigma), 10 mg of propylparabens (Nipa Laboratories, UK) and 0.25 ml of phenylethyl alcohol were transferred to the volumetric flask containing the meloxicam. Approximately 30 ml of boiled and cooled water for injections was added to the flask, which was placed into an ultrasonic bath and sonicated until the contents had dissolved. Ice was added to the ultrasonic bath if the temperature exceeded 35°C. The solution was made up to volume with boiled and cooled water. The final solution had a pH of 8.75 and an osmolality of 0.501 osmol/kg.

Example 7 - Solution containing approximately 37.5 mg/ml meloxicam and 150 mg/ml poloxamer 188 (Formulation B)

This solution was prepared as described in Example 6, except 7.5 g of poloxamer 188 was used in place of 7.5 g of poloxamer 407. The final solution had a pH of 8.73 and an osmolality of 0.518 osmol/kg. Example 8 - Solution containing approximately 37.5 mg/ml meloxicam and 150 mg/ml PEG 8000 (Formulation C)

This solution was prepared as described in Example 6, except 7.5 g of PEG 8000 (Sigma) was used in place of 7.5 g of poloxamer 407. The final solution had apH of 8.88 and an osmolality of 0.529 osmol/kg.

Example 9 - Solution containing approximately 37.5 mg/ml meloxicam solution, 150 mg/ml PEG 8000 and 20 μl/ml benzyl alcohol (Formulation D)

1.875 g of meloxicam was weighed into a 50 ml volumetric flask and 5.87 ml of meglumine solution (Example 6) added. 7.5 g of PEG 8000, 50 mg of EDTA disodium, 10 mg of propylparabens and 1 ml of benzyl alcohol were transferred to the volumetric flask containing the meloxicam. Approximately 30 ml of boiled and cooled water for injections was added to the flask, which was placed into an ultrasonic bath and sonicated until the contents had dissolved. Ice was added to the ultrasonic bath if the temperature exceeded 35°C. The solution was made up to volume with boiled and cooled water. The final solution had a pH of 8.82 and an osmolality of 0.638 osmol/kg.

Example 10 - Solution containing approximately 55 g/mϊ meloxicam and 150 mg/ml poloxamer 188 (Formulation E)

2.75 g of meloxicam was weighed into a 50 ml volumetric flask and 8.61 ml of meglumine solution (Example 6) added. 7.5 g of poloxamer 188, 50 mg of EDTA disodium (Sigma, Poole, UK), 10 mg of propylparabens (Nipa

Laboratories, Pontypridd, UK) and 0.25 ml of phenylethyl alcohol were transferred to the volumetric flask containing the meloxicam. The formulation was completed as described in Example 11. The final solution had a pH of 8.96 and an osmolality of 0.648 osmol/kg.

Example 11 - Solution containing approximately 55 mg/ml meloxicam solution, 150 mg/ml poloxamer 188 and 20 μl/ml benzyl alcohol (Formulation F)

2.75 g of meloxicam was weighed into a 50 ml volumetric flask and 8.61 ml of meglumine solution (Example 6) added. 7.5 g of PEG 8000, 50 mg of EDTA disodium (Sigma, Poole, UK), 10 mg of propylparabens and 1 ml of benzyl alcohol (Sigma) were transferred to the volumetric flask containing the meloxicam. The formulation was completed as described in Example 9. The final solution had a pH of 9.10 and an osmolality of 0.739 osmol/kg.

Example 12 - Solution containing approximately 55 mg/ml meloxicam and 175 mg/ml poloxamer 188 (Formulation G)

2.75 g of meloxicam was weighed into a 50 ml volumetric flask and 8.61 ml of meglumine solution (Example 6) added. 8.75 g of poloxamer 188, 50 mg of EDTA disodium (Sigma, Poole, UK), 10 mg of propylparabens and 0.25 ml of phenylethyl alcohol were transferred to the volumetric flask containing the meloxicam. The formulation was completed as described in Example 9. The final solution had a pFI of 8.99 and an osmolality of 0.845 osmol/kg. Example 13 - Solution containing approximately 55 mg/ml meloxicam and 150 mg/ml poloxamer 407 (Formulation H)

This solution was prepared as described in Example 10, except 7.5 g of poloxamer 407 was used in place of 7.5 g of poloxamer 188. The final solution had a pH of 8.84 and an osmolality of 0.604 osmol/kg.

Example 14 - Solution containing approximately 55 mg/ml meloxicam solution, 150 mg/ml poloxamer 407 and 20 μl/ml benzyl alcohol (Formulation I)

This solution was prepared as described in Example 11, except 7.5 g of poloxamer 407 was used in place of 7.5 g of poloxamer 188. The final solution had a pH of 8.86 and an osmolality of 0.684 osmol/kg.

Example 15 - Solution containing approximately 55 mg/ml meloxicam and 175 mg/ml poloxamer 407 (Formulation J)

This solution was prepared as described in Example 12, except 8.75 g of poloxamer 407 was used in place of 8.75 g of poloxamer 188. The final solution had apH of 9.00 and an osmolality of 0.768 osmol/kg.

Example 16 - Solution containing approximately 55 mg/ml meloxicam and 175 mg/ml PEG 3405, (Formulation K)

This solution was prepared as described in Example 12, except 8.75 g of PEG 3405 (BASF Pharma, Germany) was used in place of 8.75 g of poloxamer 188. The final solution had a pH of 8.99 and an osmolality of 0.913 osmol/kg. Example 17 - Solution containing approximately 55 mg/ml meloxicam, 200 mg/ml hydroxypropyl-β-cycϊodextrin and 50 mg/ml poloxamer 188 (Formulation L)

2.75 g of meloxicam was weighed into a 50 ml volumetric flask and 8.61 ml of meglumine solution (Example 6) added. 10 g of hydroxypropyl-β- cyclodextrin, 2.5 g of poloxamer 188, 50 mg of EDTA disodium and 0.5 ml of 15 mg/ml benzalkonium chloride solution were transferred to the volumetric flask containing the meloxicam. Approximately 30 ml of boiled and cooled water for injections were added to the flask, which was placed into a sonic bath and sonicated until the contents had dissolved. Ice was added to an ultrasonic bath if the temperature exceeded 35°C. The flask contents were made to volume with boiled and cooled water. The final solution had a pH of 8.86 and an osmolality of 0.591 osmol/kg.

Example 18 - Stability of samples

Formulations A to L, as described in Examples 6-17, were analysed for meloxicam content by HPLC and then dispensed in 2.7 ml aliquots into 5 ml clear glass injection vials, which were overlaid with nitrogen and sealed with elastomer closures and metal overseals. The vials were placed into storage incubators at 2-8°C, 25°C and 40°C. After 1, 3, 6, 9 and 12 months, samples of the formulations were removed from their storage incubators and the appearance noted and meloxicam content measured (HPLC). These data are summarised in Table 3.

^a = 2-8°C; ^b = 25^oC; ^c = 40°C. * Precipitate present

The visual appearance and drug content of all of the solutions containing 37.5 mg/ml meloxicam (Foπnulations A-D) remained unchanged during the 12 month stability evaluation. The inclusion of benzyl alcohol as an additional solubiliser in Formulation D therefore appeared to be of no benefit. At 1 month a thick precipitate appeared in Formulations H, I, J and K stored at 2-8°C and, as a consequence, these were removed from the stability study. The appearance of a precipitate was indicative of physical instability in the solutions. In Formulations E and G, a precipitate was evident in solutions stored at 2-8 °C for the majority of the analysis time points. Formulations F and L were more satisfactory and a precipitate was present at 2-8°C at only a minority of time points. Hence, the additional inclusion of a cyclodextrin or benzyl alcohol was necessary to produce a stable solution containing 55 mg/ml meloxicam. The general absence of a precipitate in Formulation F (contained poloxamer 188) compared to Formulation I (poloxamer 407) indicated that including poloxamer 188 was advantageous in a high concentration meloxicam composition.

Example 19 - Effect of PEG molecular weight on solution osmolality

50 mg/ml aqueous solutions of PEG 400, 3350 and 8000 were prepared by weighing 0.5 g of the PEG into a 10 ml volumetric flask, adding approximately 8 ml of water, mixing to dissolve and then making up to volume with water. The osmolality of each solution was measured and values are recorded in Table 4 below: Table 4. Effect of PEG molecular weight on solution osmolality

The results illustrate that the osmolality of PEG aqueous solutions increases as the molecular weight of the PEG decreases. Example 20 - Preparation of meloxicam solutions containing PEG 400 vs. PEG 8000

Stock solutions of PEG 400 (Sigma) and PEG 8000 were prepared by weighing 2 g of the PEG into a 10 ml volumetric flask dissolving in approximately 7 ml of water and then making up to volume with water. 75 mg of meloxicam was weighed into each of four glass vials. To each of two of the vials was added 0.56 ml of 1M meglumine solution. To each of the remaining two vials was added 0.56 ml of 1M lysine solution (prepared by weighing 1.492 g of lysine [Sigma] into a 10 ml volumetric flask and dissolving in and making to 10 ml with water). The meloxicam samples were stirred to form suspensions. 1 ml of PEG 400 solution was added to one of the suspensions in meglumine and one in lysine. 1 ml of PEG 8000 solution was added to each of the remaining samples. After stirring, each of the samples of meloxicam had dissolved to form a clear solution and contained 48 mg/ml meloxicam and 128 mg/ml of PEG. The osmolality of the solutions was measured and are recorded in Table 5.

Table 5. Osmolality of meloxicam solutions containing PEG 400 arid PEG 8000

These data show that PEG 8000 and PEG 400 are both able to solubilise meloxicam to the same extent, but the higher molecular weight PEG has the advantage of producing solutions with a lower osmolality which will be better tolerated (less irritant) when administered into the nasal cavity.

Claims

Claims:

1. An aqueous composition for nasal administration comprising: (i) from 26 to 120 mg/ml of meloxicam; (ii) a base; and (iii) a solubility enhancing agent.

2. A composition according to claim 1, wherein the base is an organic base.

3. A composition according to claim 2, wherein the base is tromethamine, meglumine or lysine.

4. A composition according to claim 3, wherein the base is meglumine.

5. A composition according to any one of the preceding claims, wherein the base is present in an amount of from 0.9 to 1.4 moles per mole of meloxicam..

6. A composition according to any one of the preceding claims comprising from 30 to 90 mg/ml of meloxicam.

7. A composition according to any one of the preceding claims, wherein the solubility enhancing agent is a poloxamer and/or a polyethylene glycol.

8. A composition according to claim 7 comprising poloxamer 188 or poloxamer 407.

9. A composition according to claim 7 or claim 8, comprising a poloxamer in a concentration of from 50 to 250 mg/ml.

10. A composition according to claim 7, wherein the polyethylene glycol has an average molecular weight of 8000.

11. A composition according to claim 7 or claim 10, comprising a polyethylene glycol in a concentration of from 50 to 250 mg/ml.

12. A composition according to any one of the preceding claims, additionally comprising cyclodextrin and/or benzyl alcohol.

13. A composition according to claim 1, comprising from 30 to 49 mg/ml of meloxicam; tromethamine, meglumine or lysine; and from 50 to 250 mg/ml of a poloxamer or 50 to 250 mg/ml of a polyethylene glycol having an average molecular weight of from 3000 to 10000.

14. A composition according to claim 13, comprising from 30 to 40 mg/ml meloxicam, from 16 to 27 mg/ml meglumine and from 100 to 200 mg/ml poloxamer 407 or from 100 to 200 mg/ml PEG 8000.

15. A composition according to claim 1, comprising from 50 to 120 mg/ml of meloxicam; meglumine or lysine; from 50 to 250 mg/ml of a poloxamer or from 50 to 250 mg/ml of a polyethylene glycol; and from 5 to 500 mg/ml of a cyclodextrin or from 5 to 30 μl/ml of benzyl alcohol.

16. A composition according to claim 15, comprising from 50 to 60 mg/ml meloxicam, 27 to 40 mg/ml meglumine, 40 to 160 mg/ml poloxamer 188 and 150 to 250 mg/ml HP-β-CD or 15 to 25 μl/ml benzyl alcohol.

17. A process for producing a composition as defined in any one of the preceding claims, which process comprises mixing the components in water and optionally sonicating the mixture.

18. The use of a base and a solubility enhancing agent in the manufacture of an aqueous composition for nasal administration comprising from 26 to 120 mg/ml of meloxicam.

19. The use of a base and a solubility enhancing agent in the manufacture of an aqueous composition for nasal administration comprising from 26 to 120 mg/ml of meloxicam for the treatment or management of pain, osteoarthritis, rheumatoid arthritis ^~ or ankylosing spondylitis.

20. The use of a composition as defined in any one of claims 1 to 16 in the manufacture of a medicament for the treatment or management of pain, osteoarthritis, rheumatoid arthritis or ankylosing spondylitis.

21. A method of administering meloxicam to a patient in need thereof, which method comprises the intranasal administration of a composition as defined in any one of claims 1 to 16.

22. A method of treating or managing pain, osteoarthritis, rheumatoid arthritis or ankylosing spondylitis, which method comprises the intranasal administration of a composition as defined in any one of claims 1 to 16.

3. A nasal delivery device or a dose cartridge for use in a nasal delivery device comprising a composition as defined in any one of claims 1 to 16.