The present invention relates to coated granules of spheroidal shape with optimised performance.

The use of enteric coating as a method to bypass the gastric environment is well known. The rationale for the pharmaceutical use of such formulations has been either to protect the gastric mucosa from local damage caused by the drug or to protect the drug from possible decomposition by the gastric fluid. A typical example of a drug which may cause local damage of the gastric mucosa is aspirin. It has been shown, however, that similar mucosal damage is caused by other non-steroidal anti-inflammatory drugs such as naproxen and ketoprofen.

A potential drawback with the use of enteric coated tablets is related to the variations in the delay between administration and gastric emptying, which are dependent on whether the tablet is taken together with food or not. Non- disintegrating single unit dose forms remain in the stomach until the end of the digestion phase and are only then cleared from the stomach and through the terminal ileu by the migrating myoelectric complex. However, because of wide variations in the timing of gastric emptying, the onset of the effect of the drug is often unpredictable.

In order to overcome this disadvantage, enteric coated granules have been introduced. Such granules of less than 2mm diameter are delivered through the pylorus together with food.

Conventionally produced core granules are normally of different shape and size, including some hard-edged shapes, and this makes it difficult to provide an even coating. As a result, more coating material is needed to provide the required resistance against the gastric fluid. Normally, a release of up to 5% of the active material occurs after two hours in artificial gastric fluid at pH 1, even with a relatively ^" heavy coating. With such preparations, it is difficult to obtain complete protection of the gastric mucosa.

The present invention is based on the concept that the core granules should be of much more even size distribution and more precisely spheroidal shape, thus enabling the enteric coating to be of more uniform thickness. By avoidance of thin spots on the coated granules, the release of active substance into the gastric fluid can be minimised and by the avoidance of thick spots, the overall amount of coating can be optimised.

According to the present invention, we provide enteric coated granules in which the core granules comprising an active substance are substantially all essentially spheroidal, with mean variations between maximum and minimum diameters less than 10% of the maximum diameter, the coated granules showing variations in maximum diameter not greater than 15%, the mean value of said maximum diameters being between 0.5 and 2.0mm, preferably between 0.5 and 1.5mm, said granules dissolving in an aqueous medium only at a pH of 5.5 or higher.

The coated granules according to the invention have given specially good results in terms of resistance to gastric dissolution, e.g. at pH 1, and rapid dissolution in the gut, e.g. at pH 7.5 (see Tables I and III hereinafter).

According to a further aspect of the invention, therefore, we provide enteric coated granules which release not more than 0.5% by weight of active substance after two hours in an aqueous medium at pH 1.0 and which release more than 50% by weight of the active substance after 50 minutes in an aqueous medium at pH 7.5, preferably more than 50% by weight after 45 minutes in such a medium.

It has been shown that the basal gastric pH can be surprisingly high. In some, presupposed healthy, individuals neutral values have been measured in fasting conditions. Normally the gastric content has a pH value between 1-3 and a transient rise to about 5 after a meal.

The gastric-resistant coating of potentially irritant drugs such as NSAIDs ought to resist transient rises in pH in order to prevent drug leakage in the stomach.

As a further aspect of the present invention, and in order to obtain pharmaceutical products with improved properties, the granules may be coated with selected coating materials which dissolve at pH 6 or higher. Coating materials dissolving at pH 6.5 or greater are even more preferred.

Table III hereinafter shows the formulae of coating liquids where various anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L, S and mixtures of L and S) have been used. Eudragit L (50% methacrylic acid) dissolves at pH 6 or higher and Eudragit S (30% methacrylic acid) dissolves at pH 7. By using combinations of Eudragit L and S, coatings which start to dissolve between pH 6 and 7 can be produced. Eudragit

30D is a copolymer of 50% methacrylic acid and 50% acrylic acid methyl ester which dissolves at pH 5.5.

Table III and Figure 1 hereinafter show the dissolution profiles of naproxen granules coated with the above Eudragit combinations, presented in Table II.

The invention is of particular use in the formulation of non-steroidal anti-inflammatory drugs (NSAID) having an adverse action on the gastric mucosa, for example diclofenac, ketoprofen, ibuprofen piroxicam or, more particularly, naproxen.

The granules according to the invention may be produced by subjecting an appropriate formulation of the active drug, for example an admixture with a diluent or excipient such as lactose, to granulation and spheroid formation, e.g. using an extruder combined with a spheronizer, or rotor granulator technology, to form the required spheroids. Spheroidal granules so produced are rigorously examined and graded to retain only those which fall within the above limits, using appropriate sieves and microscopic sampling to determine spheroidal shape. The graded spheroidal granules are coated, for example in a fluid bed coater, e.g. with cellulose acetate phthalate or poly ethacrylate esters (Eudragit L, S or 30 D) containing small amounts of plasticizers such as polyols or organic esters, to give enteric coated granules of improved resistance against gastric fluid and with excellent rate of release in the small intestine (see Table I and Table III hereinafter) . The mean coating thickness is preferably in the range 20 to 25 microns.

TABLE I

Dissolution rate of naproxen granules (1) , mean diameter 1.2mm, and piroxicam granules (2), mean diameter 1.05mm, coated with 7.5% "Eudragit L 30 D" (calculated as dry lacquer substance)

* Phosphate Buffer pH 6.8

The following Example is given by way of illustration only:

(a) Composition of naproxen spheroids:

Naproxen 500 g

Lactose 90 g

The ingredients were premixed and 200ml of deionised water was added. After 5 minutes of mixing, the moist mass was granulated through an extruder and than processed to spheroidal granules in a spheronizer. Only those granules were retained which were within the size limits 1.0 to 1.4mm and which, on sampling, had a mean variation in maximum diameter not greater than 15% and variations between maximum and minimum diameter of about 7%.

(b) Coating of naproxen spheroids:

Coating compositions according to Table II hereinafter were applied to the spheroidal granules of stage (a) .

The spheroidal granules were coated with the above dispersions in a fluid bed coating apparatus (wherein the particles were suspended in an upward vertical air flow during the coating procedure) to give uniformly coated granules having a mean calculated coating thickness of 20 microns.

The coated granules conformed to the following in vitro dissolution criteria:

2 hours at pH 1 not greater than 0.5%

50 minutes at pH 7.5 more than 50%

Further details are given in Table III hereinafter

Table II : Formula of coating solution

Amounts of ingredients Example (% w/w) :

B D E

Eudragit L 30 D 15,0 (1)

Eudragit L 6,0 4,5 3,0

Eudragit S 1,5 3,0 6,0

Polyethylene glycol 400 1,5

Triacetin 1,5 1,5 1,5 1,5

Talc 3,5 2,8 2,8 2,8 2,8

Water 80,0

Ethanol 89,7 89,7 89,7 89,7

(1) Calculated as dry substance

Table III Gastric resistance, lag time and dissolution rate of Naproxen granules, mean diameter 1,2mm, coated with 10% of various Eudragit brands

Typical dissolution curves in phosphate buffer at pH 7.5 are given in Figure 1 (USP is United States Pharmacopeia) .

The naproxen in the above formulations may be replaced by piroxicam, or other NSAIDs.

The granules according to the invention are preferably presented in gelatine capsules, which rapidly dissolve in the stomach. The granules may alternatively be presented mixed with suitable excipients to form dispersions.