IE20100230A1 - A process for the preparation of an orally administered unit dose tablet - Google Patents

Abstract

The present invention is directed to a process for preparing an orally administered palatable unit dose tablet comprising naratripan, lactose anhydrous, a first microcrystalline cellulose and second microcrystalline cellulose, croscarmellose sodium, magnesium stearate wherein the process comprises the preparation of a core tablet and coating the core tablet followed by collecting and packaging the coated unit dose tablets.

Description

“A PROCESS FOR THE PREPARATION OF AN ORALLY ADMINISTERED UNIT DOSE TABLET’ The present invention is directed to a process for preparing an orally administered palatable unit dose tablet comprising naratriptan and to an orally administered palatable unit dose tablet comprising naratriptan.

Naratriptan is a triptan drug used for the acute treatment of migraine attacks. It is a selective 5-hydroxytryptamine1-receptor subtype agonist.

Naratriptan hydrochloride is white to pale yellow crystalline powder that is readily soluble in water (approximately 35 mg/ml at 25°C) and has the following structural formula: ibtciAL·) Naratriptan has been shown to be a selective agonist for 5 hydroxytryptaminel (5-HT, id/ib) receptors mediating vascular contraction. This receptor is found predominantly in intracranial (cerebral and dural) blood vessels. Naratriptan has high affinity for human cloned 5-HT1B and 5-HT1D receptors; the human 5-HT1B receptor is thought to correspond to the vascular 5-Ι-ΠΤ receptor mediating contraction of intracranial blood vessels. Naratriptan has little or no effect at other 5-HT receptor (5-HT2f 5-HT3i 5-HT4 and 5-HT7) subtypes.

Naratriptan is used as an anti-migraine treatment. In animals, naratriptan selectively constricts the carotid arterial circulation. This circulation supplies blood to the IE 1 0023 0 extracranial and intracranial tissues such as the meninges, and dilatation and/or oedema formation in these vessels is thought to be the underlying mechanism of migraine in man.

The present invention is directed to an improved large-scale process for the production of an orally administered unit dose tablet comprising naratriptan.

According to a first aspect of the invention, there is provided a process for the preparation of an oraily administered naratriptan unit dose coated core table wherein the core tablet comprises naratriptan hydrochloride from approximately 1 to 2.5% w/w based on the total weight of the core tablet of wherein 90% of the naratriptan hydrochloride particles are less than 150 microns, 50% of the naratriptan hydrochloride particles are less than 50 microns and 10% of the naratriptan hydrochloride particles are less than 20 microns; lactose anhydrous from 30 to 55% w/w based on the total weight of the core tablet wherein 100% of the particles are less than 250 microns, 50% of the particles are less than 150 microns, and 10% of the particles are less than 50 microns; a first microcrystalline cellulose and second microcrystalline cellulose with a combined weight from 20 to 90% w/w based on the total weight of the core tablet wherein the first microcrystalline cellulose has 90% of the particles less than 250 microns, 50% of the particles less than 150 microns, and 10% of the particles less than 50 microns; the second microcrystalline cellulose has 90% of the particles less than 150 microns, 50% of the particles less than 100 microns, and 10% of the particles less than 25 microns; croscarmellose sodium from 0.5 to 5% w/w based on the total weight of the core tablet wherein 90% of the particles have a particles size less than 100 microns and a 50% of the particles have a particle size less than 75 microns; and IE 1 0 0230 magnesium stearate from 0.5 to 1% w/w based on the total weight of the core tablet; and the coating comprises an aqueous-based film-coated solution comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and one or more colouring agents; wherein the process comprises the following steps i) the preparation of a core tablet comprising: weighing a pre-determined amount of the active ingredient naratriptan hydrochloride and each of the excipients lactose anhydrous, microcrystalline cellulose, croscarmellose sodium and magnesium stearate; dividing the magnesium stearate into a first and second portion; adding naratriptan hydrochloride and the first portion of magnesium stearate and blending; adding the first and second microcrystalline cellulose in a sequential manner and blending; adding lactose anhydrous and croscarmellose sodium and blending; sieving the blended ingredients through a 40 mesh sieve; blending the sifted material for approximately 20 to 30 minutes; sieve the second portion of the magnesium stearate through a 20 mesh sieve and adding the sifted magnesium stearate to the sifted material from the previous step; blending for a further 5 to 10 minutes to form a blended mixture; IE 1 002 3 0 subjecting the blended mixture to a direct compression step comprising feeding the blended mixture into drums and transferring the mixture into a hopper; feeding the mixture from the hopper into a die cavity of a compression table press; forming core tablets under direct compression to achieve unit dose tablets with a friability of less than 1%, a disintegration time of less than 15 minutes and a hardness of 50 to 150N; discharging the core tablets from the press and transferring the tablets into a coating drum; and ii) coating the core tablet comprising the steps of: preparing an aqueous based film coating solution comprising polyvinyl alcohol, titanium dioxide, macrogol/poiyethylene glycol, talc and at least one colouring agent; coating the unit dose tablets with the film coating solution in a drum to achieve a target weight gain equivalent to 3.5 % of the core tablet weight; collecting and packaging the coated unit dose tablets.

Accordingly, the present invention is directed to a large-scale process for the manufacture of naratriptan tablets to produce a tablet with little product variation, in terms of uniformity of content of the tablets, hardness, disintegration and dissolution patterns, within each batch. The tablet of the invention is immediate release oral dosage form.

The active ingredient naratriptan only required at low levels. Specifically, naratriptan is used at a level less than approximately 2.5% w/w, preferably less than 1.5% w/w based on the weight of the coated tablet. Ideally, the unit dose table comprises 2.5mg Naratriptan as this is an effective amount of the potent active ingredient. The unit dose IE 1 0 0230 tablet of the invention is an immediate drug-release product where the active substance is released within approximately 45 minutes The use of an active ingredient at this low level presents various processing problems in terms of obtaining tablets with optimum disintegration rate characteristics, friability, dissolution patterns and optimum dose, when particularly when manufactured on a largescale. The present invention aims to addresses these processing issues.

When the active ingredient is at this low level, the excipients must be carefully chosen so as to result in a pharmaceutically acceptable immediate release oral dosage form. The choice of the particular ingredients and excipients ensures that a uniform and homogenous tablet is formed.

Additionally, the active ingredient naratriptan itself exhibits poor flow properties due to its fine particle size. Thus, the choice of manufacturing process is critical so that the active ingredient can be processed efficiently and correctly. For example, the use of a direct compression as explained below aids the processing of naratriptan. Furthermore, geometric mixing during the processing assists in the mixing of the ingredients which have poor flow properties such as the active ingredient.

Another major challenge in this large-scale manufacture of a unit dose table is to formulate a homogenous blend or granule that will remain homogenous during the compression process. Wet granulation is usually used to deal with this aspect. However, wet granulation involves additional processing steps, high product loss during the process, and it can cause some degradation of the active ingredient, which is undesirable when manufacturing on a large scale. Thus, the present invention utilizes direct compression. This is designed to overcome the complications caused by wet granulation whilst still resulting in a uniform and homogenous tablet. In addition, direct compression is required so that one of the excipients, anhydrous lactose can be processed. Wet granulation cannot be used with this particular excipient.

However, the use of direct compression presents problems when manufacturing uniform tablets with high homogeneity when the level of active ingredient is low. In order to deal with this problem, the selection of the correct excipients and in particular the particle size ύ of the excipients was essential. Similarly the particle size distribution of active ingredient was also critical to improve the uniformity of blend in the formulation.

The following table outlines the specific active ingredient and excipients used in the unit 5 dose tablet of the invention.

Ingredient Preferred Amount (% w/w) based on the total weight of the core Example Amount (% w/w) based on the total weight of the core Average Particle size distribution Naratriptan hydrochloride (Active) Approx. 1.0 to 2.5% 1.0 to 1.5 d10 = 20p d50= 50μ d90= 150μ Tablet core excipients: Lactose anhydrous (filler) Approx. 30 to 55% Approx. 30 to 40% d10 = 50μ d50= 150μ d100= 250μ Microcrystaliine cellulose 1 (pH102) (filler) Approx. 20 to 90% combined total Approx. 20 to 30% d 10 = 50μ d50= 150μ d90= 250μ Microcrystaliine cellulose 2 (pH 101) (filler) Approx. 20 to 40% ά10 = 25μ d50= 100μ d 90= 150μ Croscarmellose sodium (disintegrant) Approx. 0.5 to 5% Approx 1.5 to 2% d 50 = 75μ d90= 100μ Magnesium Stearate (lubricant) Approx 0.5 to 5% Approx 0.5 to 1 % As explained above the particle size of the naratriptan hydrochloride is an essential 10 feature of the invention. Approximately 2.78 mg of Naratriptan Hydrochloride is equivalent to 2.5 mg of the active ingredient Naratriptan.

IE 1 Ο Ο2 5 Ο A combination of two fillers was used, lactose anhydrous and microcrystalline cellulose, ideally in a ratio of approximately 40:60.

The first filler, lactose anhydrous when used in direct compression, aids oral dosage 5 formulations in terms of blend homogeneity, compactibility, consistent bulk density and flow. Ideally, a level of approximately 30 to 55% w/w, preferabiy 30 to 40% w/w, more preferably 36% w/w is used.

The second filler, microcrystalline cellulose also aids the flow and compactibility of dry f0 powder formulations. It compacts well, under minimum compression pressures and has high binding capability. It also positively influences the resistance to crushing and friability of tablets, yet allows tablets to disintegrate rapidly. Other advantages include inherent lubricity and the highest dilution potential of all binders. These properties make microcrystalline cellulose particularly valuable as a filler and binder in the present invention.

Ideally, the total level of microcrystalline cellulose is approximately 20 to 90% w/w, preferably 20 to 60%, more preferably 56% w/w. We propose the use of two types of microcrystalline cellulose which differ in terms of particle size. The smaller particle sized microcrystalline cellulose is used to improve the flow and the uniformity of blend, the larger sized microcrystalline cellulose is used to further improve the blend. Specifically, microcrystalline cellulose 1 (pH101) has a very small particle size and close to active ingredient particle size. This assists the processing of the active ingredient, e.g. useful for geometric dilution process. Specifically, during processing the active ingredient is slowly loaded onto the microcrystalline cellulose 1 (pH 101) particles. The can be geometrically increased to include higher particle size excipients until the ideal uniform mix is reached with proper dilution.

The disintegrant used was croscarmellose sodium. Ideally, it is used at a level of 0.5 to % w/w, preferably 1.5 to 2% w/w, prefably 2% w/w.

The lubricant used is magnesium stearate. It is used as a lubricant to avoid sticking problems during compression in addition to its properties result in a smooth surface tablet. Magnesium Stearate is used in the proposed naratriptan formulation at a level of IE 1 00230 approximately 0.5% to 5% w/w, preferably 0.5 to 1%, more preferably 0.8%, Ideally, it has a maximum specific surface area of 3500 m2/g.

Once the core tablet is made, it is then coated. The following table outlines the tablet film coating excipients: Tablet film coating excipients: Preferred Amount (% w/w) Example Amount (% w/w) Polyvinyl alcohol Approx. 30 to 40% 40 Titanium dioxide Approx. 20 to 30% 23 Polyethylene glycol Approx. 15 to 25% 20 Talc Approx. 10 to 20% 15 Colouring agent e.g. Iron Oxide yellow and indigo carmine Aluminium lake Approx. 0.1 to 10% 2 The film forming agent comprises PVA, polyethylene glycol, titanium dioxide and colouring agents.

The film forming agent acts as a taste-masking agent, aids the friability of the product, and protects the tablet from air and moisture. Ideally, it is mixed with water in a ratio of 5:1 water:excipients However, the water is dried off during the coating process.

Polyethylene glycol is used in as plasticizer in film-coating suspension.

Talc is used in for anti-caking properties in film-coating suspension.

Titanium Dioxide is used as a white pigment in the proposed formulation to give the film coat an opacity appearance.

JE 1 002 3 0 Various colouring agents may be used, including iron oxide yellow and Indigo Carmine Aluminium Lake are used in the film coating suspension of the proposed formulation in combination to give the film coat the green colour.

The invention is not limited to the embodiments described above but may be varied within the scope of the claims.

The invention will now be described by reference to the following non-limiting examples and figures.

Figure 1 shows a flowchart for the manufacture of a unit dose tablet.

The steps 1 to 5 relates to the preparation of a core tablet.

Prior to commencing the manufacturing methods a pre-determined amount of the active ingredient naratriptan hydrochloride and each of the excipients lactose anhydrous, a first and second microcrystalline cellulose, croscarmellose sodium and magnesium stearate are weighed. The magnesium stearate is divided into a first and second portion.

In step 1, naratriptan hydrochloride is added to the first portion of magnesium stearate and subjected to a blending step.

In step 2, geometric proportions of the first and second microcrystalline cellulose is added to the mixture from step one and subjected to a blending step.

In step 3, lactose anhydrous and croscarmellose sodium are added to the mixture from step two and subjected to a blending step. The resultant mixture is sieve blended through a 40# mesh sieve or equivalent and subjected to further blending step. Ideally this blending step takes place for approximately 20 to 30 minutes.

In step 4, the second portion of the magnesium stearate is added through a 20 mesh sieve to the mixture from step 3 and subjected to a blending step for a further 5 to 10 minutes to form a blended mixture.

IE 1 0 02 3 0 The blended mixture is then subjected to a compression step to form a unit dose tablet. This involves subjecting the blended mixture to a direct compression step comprising feeding the blended mixture into drums and transferring the mixture into a hopper. The mixture is then fed from the hopper into a die cavity of a compression table press. Core tablets are then formed. Under direct compression to achieve unit dose tablets with a friability of less than 1%, a disintegration time of less than 15 minutes and a hardness of 50 to 150N. The core tablets are discharged from the press and transferred the tablets into a coating drum.

Finally, in step 5 the unit dose tablets undergo a film-coating step. This coating step comprises preparing an aqueous based film coating solution comprising polyvinyl alcohol, titanium dioxide, macrogol/poiyethylene glycol, talc and at least one colouring agent. The unit dose tablets are coated with the film coating solution in a drum to achieve a target weight gain equivalent to 3.5 % of the core tablet weight.

Ideally the coating step comprises transferring the coating solution to a solution holding tank; transferring the tablets to a coating pan and heating to a bed temperature of approximately 35 to 55°C; spray coating the tablets at a spray rate of 35 to 40 g/min until the core tablets are film-coated to a target weight gain of approximately 3.5 % of the core tablet weight; removing the coating tablets to a drying station for approximately 10 to 20 mins at 55°C; cooling the tablets to 25°C; and transferring the coated tablets to a double polyurethane lined container prior to packaging.

After this coating step, the coated tablets are collected and packaged.

IE 1 002 3 0 EXAMPLE Manufacture of Naratriptan 2.5mg tablets MATERIALS Equipment Operation Blender - double cone blender, winkworth drum tumbler machine, drum blender Blending Sifter, Russel! sieve machine Sieving Compression machine Compression Coating machine Coating Ingredient %w/w Quantity per batch (kg) Average Particle size distribution Naratriptan hydrochloride (Active) 1.36* 0.3058* d 10 = 20μ d 50= 50μ d 90= 150μ Lactose anhydrous (filler) 39.71** 8.910** d10 = 45μ d50= 150μ d 90= 250μ Microcrystalline cellulose 1 (pH101) (filler) 20.34 4.565 d 10 = 30μ d50= 121 μ d 90= 215μ Microcrystalline cellulose 2 (pH102) (filler) 35.78 8.030 d 10 = 21μ d 50= 72μ d90= 148μ Croscarmelfose sodium (disintegrant) 1.96 0.4400 d 50 = 45μ d 90= 75μ Magnesium Stearate (lubricant) 0.84 0.1892 - 100 22.44 *1.36% of naratriptan hydrochloride is approximately equivalent to 1.23% w/w/of naratriptan.

The quantity of naratriptan is calculated based on the actual potency of the raw material IE 1 00230 used. Approximately 2.78 mg of Naratriptan Hydrochloride is equivalent to 2,5 mg of the active ingredient Naratriptan. “quantity of lactose anhydrous will vary based on the quantity of naratriptan hydrochloride required.

Tablet film coating excipients: Example Amount (% w/w) Polyvinyl alcohol 40 Titanium dioxide 23 Polyethylene glycol 20 Talc 1 Colouring agent e.g. Iron Oxide yellow and indigo carmine Aluminium lake 2 Water* 5:1 water to excipients ‘Purified Water Ph.Eur. used in the preparation of the coating solution is dried off during the manufacturing process METHOD Essentially, the process involves direct compression process followed by fiim-coating.

Weighing 1. Check ail materials for identity and QC approval. 2. Weigh each raw material into suitable containers Blending 3. Blend Naratriptan hydrochloride and half the quantity of Magnesium stearate Ph Eur. 4. Add in geometric proportions of Microcrystalline Cellulose (MCC) PH101 Ph. Eur. This is done to improve the flow and the uniformity of blend, and then a bigger particle size MCC pH 102 is used to further improve the blend.

IE 1 0 0 2 3 0 . Add Lactose anhydrous Ph. Eur. and Croscarmellose sodium Ph. Eur. and blend. 6. Sieve the blend through a 40 mesh sieve (or equivalent). 7. Blend the sifted material for 20 minutes. 8. Sieve the other half quantity of Magnesium stearate Ph. Eur. through a 20 mesh sieve (or equivalent). 9. Add sifted Magnesium stearate Ph. Eur. to the material from step 7 and blend for 5 minutes.

Compression . Tool compression machine with 12 mm x 5 mm capsule shaped tooling. 11. Compress the tablets to achieve the following specification: Parameter Method Specification Typical Frequency Appearance Visual inspection of tablets. A white to off white, oval shaped tablet. At set up and every 15 minutes. Average weight Determine the average weight of 20 tablets. 204 mg ±4 % Range: 196 mg - 212 mg At set up and every 15 minutes. Individual Weights Determine the individual weights of 20 tablets (Ph.Eur) 204 mg ± 7.5 % Range: 189 mg - 219 mg At set up Friability Friability as per Ph. Eur. < 1.0% At set up and every 60 minutes. Disintegration Disintegration as per Ph. Eur. <15 minutes At set up and every 60 minutes. Hardness Resistance to crushing as per Ph. Eur. 50-150 N At set up and every 15 minutes.

Coating 12. Check all materials for identity and QC approval. 13. Weigh each raw material into suitable containers properly labelled IE 1 002 30 14. Prepare the film-coating solution by mixing with purified water in a ratio of 5:1 water to excipients.

. Transfer the coating solution to the solution holding tank. 16. Film-coat the compressed tablets with the coating solution using a coating pan (RPM 4-10) and spray gun to achieve the following specification at a spray rate of 37 g/min. The tablets are heated prior to spraying to a bed temperature of approximately 35 to 55°C.

Parameter Specification Typical Frequency Appearance Green, caplet shaped, film-coated tablets. Every 15 minutes. Weight build up Target: 7.14 mg Range: 6.14 mg - 8.14 mg Every 15 minutes. 17. The core tablets are film-coated to a target weight gain of approximately .714 g per 100 tablets, equivalent to 3.5 % of the core tablet weight. Once this has been achieved spraying is stopped and the coated tablets are allowed to dry for approximately 15 minutes at 55°C and cooled to 25°C and transferred to a double polyurethane lined container. 18. Calculate the yield from the film-coating stage. 19. Samples are sent to QC for testing against the Finished Product Release Specifications.

Packaging . The tablets are packaged into blister packs such as Alu - A!u.

Quality Control Processes The following in-process controls are performed during each of the manufacturing steps: (i) Check the weight of each ingredient and record on the batch paperwork. (ii) Record the mixing times at each mixing / blending stage. (iii) Tablets are compressed according to the following parameters and data recorded according to the typical frequency2 outlined below: IE 1 0 0230 Stability Test Specification Product specifications and tests for shelf life for Naratriptan 2.5 mg film-coated tablets: Test Specification Description: Green, caplet shaped, film coated tablet. Condition of Packaging: Packaging intact. Average Weight: 211.14mg + 5 % limit. Range:200.58-221.70 mg Identification of Colour: Titanium Dioxide: oositive reaction - a vellow to oranae red colour Uniformity of dosage Units: (by Content Uniformity) The requirements are met if the acceptance value of the first 10 dosage units is less than or equal to 15.0. If the acceptance value is greater than 15.0, test the next 20 dosage units and calculate the acceptance value. The requirements are met if the final acceptance value of the 30 dosage units is less than or equal to 15.0 and no individual content of the dosage unit is less than 0.75 M or more than 1.25 M in calculation of acceptance value. Disintegration time: Not more than 30 minutes Dissolution: Sf (6 tabs) Each unit is not less than 80 % (Q + 5 %) after 15 minutes. S2: (6 tabs) Average of 12 units (Si+ S2) is equal to or greater than 75 % (Q), and no unit is less than 60 % (Q - 15 %), S3: (12 tabs) Average of 24 units (S-|+ S2+ S3) is equal to or greater than 75 % (Q), not more than 2 units are less than 60 % (Q -15 %) and no unit is less than 50 % (Q - 25 %). Assay Naratriptan: 2.5 mg ί tablet + 5 % limit Range: 2.375 - 2.625 mg / tablet (95 - 105 % of label claim) AMicrobiological Quality: As per Ph. Eur.

’Impurity 1: 1,1-dimethyl-4-[5-(2-methyl sulfamoyl ethyl)-1-H-3-indolyl]-hexahydro pyridinium chloride ’’Impurity 2: 3-(1-methyl-4-piperidyl)-5-m ethyl sulfamoyl ethyl-1 H-2-indole carboxylic acid mono hydrochloride ’’’Impurity 3:1-methyl-4-[5-(2-methyl sulfamoyl ethyl)-1-H-3-indolyl]-hexahydro-1-pyridiniumolate 10 ATest performed at initial and end of shelf life.

^Applies throughout shelf life, test conducted at release only.

IE 1 00230 Holding Times Process Stage Time Core Tablets bulk 60 days Film-Coated Tablets bulk 6 months Stability Test Results Stability Test 1 - Naratriptan 2.5 mg film-coated tablets in Alu-Alu Blisters: Packaging: Blisters composed of Aluminium blister foil and Aluminium lidding foil. Stability Protocol: The batches tested, storage conditions and time points are detailed below.

Table 1: Summary of stability batches tested, storage conditions and stability time points J Batch No: Batch size Packaging Storage conditions Time-points tested 16055C/1 110,000 tablets Alu-Alu blisters 25°C ± 2 °C, RH=60 ± 5% 0, 3, 6, 9, 12, 18, 24 & 36 months 40°C ± 2 °C, RH=75 ± 5% 0,1, 2, 3 & 6 months 16119F 110,000 tablets Alu-Alu blisters 25°C ± 2 °C, RH=60 ± 5% 0, 3, 6, 9, 12, 18, 24 & 36 months 40°C ± 2 °C, RH=75 ± 5% 0,1, 2, 3 & 6 I months Stability Test 2 - Naratriptan 2.5 mg film-coated tablets in Aclar-Alu blisters Product: Naratriptan 2.5 mg film-coated tablets in Aclar-Alu Blisters Packaging: Blisters composed of Aclar blister film and Aluminium lidding foil.

IE 1 0023 0 points Table 2: Summary of stability batches tested, storage conditions and stability time Batch No: Batch size Packaging Storage conditions Time-points Tested 16055C 110,000 tablets Aclar-Alu blisters 25°C±2°C, RH=60±5% 0, 3, 6, 9, 12, 18, 24 & 36 months 40°C±2°C, RH=75±5% 0,1, 2, 3 & 6 months 16119F/1 110,000 tablets Aclar-Alu blisters 25°C ± 2 °C, RH=60 ± 5% 0, 3, 6, 9, 12, 18, 24 & 36 months 40°C±2°C, RH=75 ± 5% 0,1, 2, 3 & 6 months Stability Test 3 Bulk Hold-Time Stability - Batches of drug product Product: Bulk Naratriptan 2.5 mg film-coated tablets Table 3: Summary of Bulk Hold-Time Stability batches tested, storage conditions and stability time points Batch No: Bulk hold Batch size Packaging Storage conditions (real time) Time- points Tested 16119F Core samples 110,000 Polyethylene Bags 25°C ± 2 °C, RH=60 + 5% 0, 30 & 60 days 16055C Coated samples 110,000 Polyethylene Bags in HDPE container 10°Cto25°C 0, 3 & 6 months II 1 oo 230 Summary of Bulk Hold-Time Stability data The bulk hold-time stability data presented to date demonstrates that bulk core and filmcoated tablets are stable when held under the above stated test conditions. Based on the available bulk hold-time stability data, a maximum bulk holding time of 60 days for the bulk core tablets and 6 months for the bulk film-coated tablets is proposed.

Summary of Stability Results The stability data in the packaging presented to date demonstrates that the product is stable under these test conditions. Based on the available stability data a shelf-life of 3 years is proposed for the product. No special storage conditions are required. No in-use storage conditions are necessary.

In vitro dissolution assay The dissolution profiles of Naratriptan tablets 2.5 mg were compared to the brand leader Naramig® tablets 2.5 mg (Glaxo Wellcome UK Ltd.).

The three media used in this in vitro dissolution assay were the standard ones: 0.1 N HCI, pH 4.5 Potassium dihydrogen orthophosphate and pH 6.8 Potassium dihydrogen orthophosphate/Sodium hydroxide. A medium volume of 500 mL was used and a basket speed of 100 rpm. All conditions were chosen in order to evaluate the release properties of the drug over the relevant physiological range.

Given the rapidly dissolving nature of the drug and rapid in vivo absorption, 0.1 N HCI is the most relevant medium for comparative purposes. The dissolution profiles in this media for both the UK and French comparators of Naramig® are provided in Figure 1 and Figure 2 below: We found that the tablets made in accordance with the present invnetino demonstrated similar in vitro dissolution behaviour, with over 95% mean dissolution at 5 minutes and nearly 100% mean dissolution at 20 minutes, to the brand leader.

IE 1 00230 Bioequivalence studies A single centre, single-dose, open-label, randomised two-period cross-over study to determine the bioequivalence of two formulations containing Naratriptan 2.5 mg (as naratriptan hydrochloride), namely 2.5 mg film-coated tablets made in accordance with the present invention and the brand leader Naramig® tablets 2.5 mg.

A total of thirty healthy, non-smoking male and female (18 males and 14 females) subjects between the ages of 18 and less than 41 years of age were enrolled into the study.

The subjects were randomly assigned dose administration in accordance with a randomisation scheme computer generated using RANDPLAN (Version 2.1). Subjects were fasted overnight for at least 10 hours (a food- and beverage-free period, with the exception of 240 mL water which was taken upon waking on clinic days, approximately 90 minutes before administration of study medication) prior to drug administration and for at least 4 hours following dosing. Dosing commenced at 07.30 hours for each period and subjects were dosed at one to two-minute intervals. On study day 1, each subject received an oral dose of Naratriptan 2.5 mg (as naratriptan hydrochloride) - one tablet of either the brand leader or the tablet made in accordance with the present invention with 240 mL water, according to the randomisation schedule. Following a 7 day washout period, all subjects returned to the clinical facility and were dosed with the alternative treatment according to the randomisation schedule.

Blood samples were obtained from an arm vein of each subject by direct venipuncture or from an indwelling catheter. Blood samples were collected pre-dose and at the following intervals (in hours) after dosing: O(pre-dose), 0.5, 1, 1.5, 2, 2.33, 2.67, 3, 3.5, 4, 5, 6, 9, 12, 14, 24 and 36 hours post30 dose in each test period.

Samples were stored frozen for analysis. Plasma samples were assayed for naratriptan by Bioanalytical Services Division of Parexel using a validated liquid chromatography IE 1 00230 method with tandem mass spectrometry (LC-MS/MS) with a calibration range of 0.0780 - 39.9 ng/mL and a lower limit of quantification of 0.0780 ng/mL.

Overall, the Naratriptan 2.5 mg film-coated tablets made in accordance with the 5 invention and the brand leader Naramig® tablets 2.5 mg were well tolerated as a singledose, administered under fasting conditions, and no significant safety issues emerged.

Claims (7)

1. A process for the preparation of an orally administered naratriptan unit dose coated core table wherein the core tablet comprises naratriptan hydrochloride from approximately 1 to 2.5% w/w based on the total weight of the core tablet of wherein 90% of the naratriptan hydrochloride particles are less than 150 microns, 50% of the naratriptan hydrochloride particles are less than 50 microns and 10% of the naratriptan hydrochloride particles are less than 20 microns; lactose anhydrous from 30 to 55% w/w based on the total weight of the core tablet wherein 100% of the particles are less than 250 microns, 50% of the particles are less than 150 microns, and 10% of the particles are less than 50 microns; 15 a first microcrystalline cellulose and second microcrystalline cellulose with a combined weight from 20 to 90% w/w based on the total weight of the core tablet wherein the first microcrystalline cellulose has 90% of the particles less than 250 microns, 50% of the particles less than 150 microns, and 10% of the particles 20 less than 50 microns; the second microcrystalline cellulose has 90% of the particles less than 150 microns, 50% of the particles less than 100 microns, and 10% of the particles less than 25 microns; 25 croscarmellose sodium from 0.5 to 5% w/w based on the total weight of the core tablet wherein 90% of the particles have a particles size less than 100 microns and a 50% of the particles have a particle size less than 75 microns; and magnesium stearate from 0.5 to 1% w/w based on the totai weight of the core 30 tablet; and the coating comprises an aqueous-based film-coated solution comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and one or more colouring agents; IE 1 0023 0 wherein the process comprises the following steps i) the preparation of a core tablet comprising: weighing a pre-determined amount of the active ingredient naratriptan hydrochloride and each of the excipients lactose anhydrous, microcrystalline cellulose, croscarmellose sodium and magnesium stearate; 10 dividing the magnesium stearate into a first and second portion; adding naratriptan hydrochloride and the first portion of magnesium stearate and blending; 15 adding the first and second microcrystalline cellulose in a sequential manner and blending; adding lactose anhydrous and croscarmellose sodium and blending; 20 sieving the blended ingredients through a 40 mesh sieve; blending the sifted material for approximately 20 to 30 minutes; sieve the second portion of the magnesium stearate through a 20 mesh sieve 25 and adding the sifted magnesium stearate to the sifted material from the previous step; blending for a further 5 to 10 minutes to form a blended mixture; subjecting the blended mixture to a direct compression step comprising feeding 30 the blended mixture into drums and transferring the mixture into a hopper; feeding the mixture from the hopper into a die cavity of a compression table press; IE 1 002 3 0 forming core tablets under direct compression to achieve unit dose tablets with a friability of less than 1%, a disintegration time of less than 15 minutes and a hardness of 50 to 1 SON; discharging the core tablets from the press and transferring the tablets into a coating drum; and ii) coating the core tablet comprising the steps of: preparing an aqueous based film coating solution comprising polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc and at least one colouring agent; coating the unit dose tablets with the film coating solution in a drum to achieve a target weight gain equivalent to 3.5 % of the core tablet weight; collecting and packaging the coated unit dose tablets.

2. The process according to claim 1 wherein the coating step comprises: transferring the coating solution to a solution holding tank; transferring the tablets to a coating pan and heating to a bed temperature of approximately 35 to 55°C; spray coating the tablets at a spray rate of 35 to 40 g/min until the core tablets are film-coated to a target weight gain of approximately 3.5 % of the core tablet weight; removing the coating tablets to a drying station for approximately 10 to 20 mins at 55°C; cooling the tablets to 25°C; and transferring the coated tablets to a double polyurethane lined container prior to packaging. IE 1 00230

3. The process according to claim 1 or claim 2 wherein the first microcrystalline cellulose is present from 20 to 50% w/w and the second microcrystalline cellulose is present from 20 to 50% w/w.

4. The process according to any of the preceding claims wherein magnesium stearate has a maximum specific surface area of 3500 m 2 /g.

5. The process according to any of the preceding claims wherein the core tablet 10 comprises: approx. 1 to 1.5% w/w of Naratriptan hydrochloride; approx. 30 to 40% w/w lactose anhydrous; approx. 40 to 60% w/w microcrystalline cellulose; 15 approx 1.5 to 2% w/w croscarmellose sodium; and approx 0.5 to 1% w/w magnesium stearate

6. The process according to any of the preceding claims comprising quality control checks throughout the process.

7. A process for the preparation of an orally administered unit dose tablet comprising a naratriptan substantially as hereinbefore described with reference to the accompanying figures and examples.