GB2355406A - A sub-lingual dosage form comprising a morphine salt - Google Patents

Abstract

A pharmaceutical preparation comprising a morphine salt together with excipients including a saccharide, a binder and a disintegrant is formulated as a solid dosage form for sub-lingual administration. The solid dosage form is formed by a wet granulation method. It is formulated for rapid dissolution to facilitate sub-lingual absorption. The morphine salt may be morphine sulphate, hydrochloride tartrate or acetate with sulphate being the most preferred. The saccharide may be lactose or mannitol or a mixture of both. The binder is preferably magnesium stearate and the preferred disintegrant is sodium starch glycolate. Other excipients such as flavouring agents, sweeteners, fillers and colouring agents may be present.

Description

2355406 ORAL DOSAGE FORM This invention relates to a pharmaceutical oral

dosage form, particularly to a formulation for administration of a morphine salt, especially morphine sulphate.

Morphine is used for control of moderate to severe pain. Morphine salts have been administered by different routes. Solutions or delay release oral formulations have been used for treatment of chronic pain, for example in cancer patients. However adverse effects include gastrointestinal disturbances and constipation. Poor absorption from controlled release buccal tablets has been reported. Controlled release formulations are difficult to administer to patients suffering from swallowing disorders.

According to a first aspect of the present invention there is provided a pharmaceutical sublingual solid dosage form comprising a morphine salt together with excipients including one or more fillers, a binder and a disintegrant.

This formulation is especially suitable for administration to patients with swallowing disorders or for paediatric use.

The morphine salt may be the sulphate, hydrochloride, tartrate or less preferably the acetate. Morphine sulphate is especially preferred.

The fillers preferably comprise soluble saccharides, for example mannitol, lactose or mixtures thereof.

A dosage form in accordance with this invention is preferably rapidly soluble when introduced into the oral cavity. However morphine salts have an unpleasant bitter taste which makes administration of a soluble dosage form unpleasant and difficult, for example to children.

The dosage form of the present invention preferably includes a saccharide selected from lactose, mannitol and mixtures thereof. The sweetness of these saccharides reduces the unpalatable taste of the active ingredient. The saccharide or saccharides used are preferably rapidly soluble in saliva. A dissolution time of about two minutes or less is preferred.

Rapid dissolution of the dosage form which is necessary to facilitate sublingual absorption may be achieved by selection of an appropriate method of tablet manufacture. Use of direct compression or dry granulation has been found to be less suitable than wet I granuiation, due to the high bulk density and electrostatic properties of morphine salts, for example morphine sulphate and excipients.

According to a second aspect of the present invention, a method of manufacture of a pharmaceutical solid dosage form of a morphine salt comprises the steps of:

mixing the morphine salt with one or more excipients selected from saccharides, disintegrants and binders; wet granulating the mixture; milling, drying and sieving the resultant granules.

Granulation may be carried out using water or an aqueous solvent mixture.

Tablets of the present invention preferably comprise compacted granulates together with an extra-granular disintegrant and a minimal quantity of an extra-granular lubricant.

Suitable disintegrants include starches such as maize starch and rice starch, crosslinked N-,vinyl-2-pyffolidone (CLPVP), sodium starch glycolate, croscarmelose sodium and formaldehyde casein or combinations thereof. A preferred disintegrant is sodium starch glycolate. The disintegrant may be present as an intra-granular disintegrant or extragranular disintegrant.

The proportion of the disintegrant may be 0. 1 to 10% of the granulate, preferably 1 to 4%, more preferably 1.5 to 2%.

Suitable lubricants include magnesium or calcium stearates or other long chain fatty acid salts. Magnesium stearate is especially preferred. A minimal proportion of lubricant is preferred, for example up to 1%, preferably about 0.8%. The lubricant may be an intragranular lubricant, extra-granular lubricant or both. Use of an extra-granular lubricant alone is preferred in order to minimise the hydrophobic properties of the dosage form.

The tablet may also include conventional excipients typically present at up to about 10% of the total tablet weight. These may include flavouring agents, for example flavourings such as menthol, peppermint, vanilla or fruit flavourings, flavouring agents typically being present up to about 0.5 to 5% by weight of the whole tablet, and sweeteners eg aspartame. Excipients may also include colouring agents, preservatives and fillers.

Preferred fillers are selected from saccharides, preferably mannitol, lactose and mixtures thereof. Mannitol may be present in an amount of 20 to 40% for example 25 to 2 30% oy weight. Lactose may be present in an amount of 40 to 60%, preferably 50 to 60% by weight.

The invention is further described by means of example but not in any limitative sense.

Amounts and percentages used in this specification are by weight unless indicated otherwise. Percentages are selected to total 100%.

Example 1

The following ingredients were formulated.

Morphine sulphate 10.000 mg Mannitol 19.000 mg Sodium starch glycollate (primojel) 1.200 mg Lactose Wharmatose (trade mark)) 100 M 38.282 mg Magnesium stearate 0.600 mg Gelatin 0.918 mg 70.000 mg A binding solution was prepared by addition of gelatin to cold purified water followed by heating on a water bath until a clear solution was obtained. Morphine sulphate, mannitol and half of the sodium starch glycolate was mixed. The homogeneous mixture was wet granulated with the binder solution. The granulates were wet sieved, dried and milled. The resultant dry granules were mixed with lactose monohydrate and the second half of the sodium starch glycolate. The lubricant was added and the final mixture was compressed to form tablets having a weight of 70 mg.

A high performance liquid chromatographic procedure was used for the quantification of morphine sulphate. A Varian Modular H Pic system was used. This consisted of a 9010 solvent delivery system, a 9050 variable wavelength UV-VIS detector operated at 290 nm, and a 9300 auto sampler equipped with a 20,ul sample loop.

3 Chromatograms were collected and integrated using a 4400 integrator. The separation was performed on a LiChrospher 100 RP - 18 (25 x 4 mm id; 5 4m) column. The mobile phase was buffer (pH 7): methanol: acetonitrile (50:10:40) at a flow rate of I ml/min. 20 I'd injections were used. The chromatography was carried out at room temperature. The eluent was monitored at 290 nm.

A standard solution was prepared by dissolving morphine sulphate RS in the mobile phase to obtain a concentration of 0.2 mg/ml.

Not less than twenty tablets were weighed and finely powdered. An amount of powder equivalent to one tablet was accurately weighed, dissolved and diluted to 50 ml with the mobile phase.

The standard and sample solutions were filtered through a 0.45'Um membrane filter and 20 gI of each sainple was injected into HPLC system.

Results Assay: 10.45 mg morphine sulphate/ling. or 104.58% of the declared amount (92.5107.5%) Content unifon-nity: max 112.43% min 94.62% (85-115%) RSD: 4. 02% (max 6%) Dissolution Test Equipment: USP 23 (with basket) Dissolution medium: 500 ml distilled water Temperature: 37'C Speed: 100 rpm Time: 5 min 4 Procedure When the system was thermostatic at 37'C. One tablet was added to each dissolution vessel. After 5 min an aliquot of 10 ml was taken from each vessel and filtered through a 0.45gm membrane filter, discarding the first ml.

Standard Preparation Exactly 20 mg of morphine sulphate RS was weighed and transferred quantitatively to a 100 ml volumetric flask. The sample was filtered through 0.45 I-zm membrane filter, discharging the first ml. The equipment and chromatographic parameters as described above were used except that the detection was at 285 nm.

Results After 2 min: 94.38% of declared amount After 5 min: 103.5 1 % of declared amount Tablets with final composition packaged in amber glass bottles with a screw cap demonstrated a good physical and chemical stability during two years period.

Claims (6)

1. A pharmaceutical sublingual solid dosage form comprising a morphine salt together with excipients including a saccharide, a binder and a disintegrant.

2. A dosage form as claimed in claim 1, wherein the morphine salt is morphine sulphate.

3. A dosage form as claimed in any preceding claim, wherein the filler comprises a soluble saccharide selected from mannitol, lactose and mixtures thereof.

A dosage form as claimed in claim 3, comprising 20 to 40% by weight of mannitol and 50 to 60% by weight of lactose.

5. A dosage form as claimed in any preceding claim, comprising granulates compacted by wet granulation.

6. A method of manufacture of a solid pharmaceutical dosage form of a morphine salt comprising the steps of mixing the morphine salt with one or more excipients selected from saccharides, disintegrants and binders; wet granulating the mixture; and milling, drying and sieving the resultant granules.

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