Spheroid formulation

Abstract: A pharmaceutical composition comprising spheroids comprising a water-soluble active ingredient or a pharmaceutically acceptable salt thereof, microcrystalline cellulose and a sugar. Preferably the active ingredient is hydromorphone hydrochloride and the sugar is lactose. Surprisingly the incorporation of a sugar improves the dissolution rate of the spheroid formulation instead of reducing the dissolution rate by competing with the active ingredient for solubilization.

Description: The present invention relates to a pharmaceutical composition for oral administration and to a process for its preparation. In particular the invention relates to a pharmaceutical composition comprising spheroids comprising a water-soluble active ingredient microcrystalline cellulose and a sugar. In the pharmaceutical art water-soluble active ingredients are conventionally formulated together with insoluble excipients in an attempt to maximise their dissolution rate. One such non water soluble pharmaceutical excipient which is widely used is microcrystalline cellulose. Microcrystalline cellulose is particularly useful in the formation of spheroids by spheronisation and can itself be processed to give spheroids by simple granulation with water followed by extrusion and spheronisation. In general, the greater the proportion of microcrystalline cellulose present in a pharmaceutical composition, the easier it is to form spheroids. Microcrystalline cellulose as an excipient generally exercises little control over the release of active ingredient from a dosage form and it would therefore be expected that compositions containing a high proportion of microcrystalline cellulose would show normal release characteristics. A normal release pharmaceutical preparation is one that achieves fast release of active ingredient in a short period of time. Conventionally a dissolution rate of 90% or more in 45 minutes would be acceptable. The present inventors have found that capsules containing spheroids comprising hydromorphone hydrochloride and a high level of microcrystalline cellulose exhibit an unacceptably slow release rate for a normal release preparation. As hydromorphone hydrochloride is highly water soluble this result is unexpected. EP-A 271,193 describes controlled release hydromorphone compositions. It is an object of the present invention to provide a normal release spheroid formulation comprising both a water-soluble salt of hydromorphone and microcrystalline cellulose which overcomes the above problems. The present inventors have surprisingly found that the incorporation of a sugar improves the dissolution rate of the spheroid formulation. Conventionally it would be expected that such a soluble excipient would reduce the dissolution rate by competing with the salt of hydromorphone for solubilization in the dissolution media (as described, for example by Lerk et al, Journal of Pharmaceutical Sciences, 68 (2), 205-210, (1979). The present invention provides a normal release pharmaceutical composition comprising spheroids comprising microcrystalline cellulose, a sugar and a pharmaceutically acceptable salt of hydromorphone having a water solubility of 1 part solute by weight in 30 parts or less of solvent the composition having an in vitro dissolution rate of the salt of at least 90% in 45 minutes. The term "spheroid" is conventional in the pharmaceutical art and means a spherical granule having a diameter of between 0.1mm and 2.5mm, especially between 0.5mm and 2mm. The active ingredient is a pharmaceutically acceptable salt of hydromorphone, particularly hydromorphone hydrochloride. The composition according to the invention preferably contains from 0.1% to 25% by weight, more preferably from 0.5 to 10% by weight, especially from 1.0 to 5.0% by weight of the pharmaceutically acceptable salt of hydromorphone, preferably hydromorphone hydrochloride. The microcrystalline cellulose used may be, for example, Avicel pH 101 or Avicel pH 102 (Trade Marks, FMC Corporation). Preferably the composition according to the invention contains from 10 to 90% by weight, preferably 25 to 75% by weight of microcrystalline cellulose. Suitable sugars for use according to the invention include water-soluble sugars such as sucrose, fructose, xylitol, sorbitol or preferably lactose. The composition according to the present invention preferably contains from 25 to 75% by weight, especially 40 to 60% by weight of the sugar. According to one preferred embodiment of the present invention the weight ratio of the microcrystalline cellulose to the sugar is between 1:3 and 3:1, especially 1:1. A particularly preferred composition according to the invention comprises spheroids comprising 1.0 to 5.0% by weight hydromorphone hydrochloride, 25 to 75% by weight microcrystalline cellulose and 40 to 60% by weight lactose. In addition the spheroids according to the present invention may also contain suitable quantities of other materials such as binders, colourants and flavourants that are conventional in the pharmaceutical art. Suitable binders include low viscosity water soluble polymers, water soluble substituted cellulose ethers such as hydroxypropylmethyl cellulose are preferred. According to a further aspect the present invention provides a process for preparing a spheroid formulation comprising (a) blending a mixture comprising microcrystalline cellulose, a sugar and a pharmaceutically acceptable salt of hydromorphone having a water solubility of 1 part solute by weight in 30 parts or less of solvent; (b) extruding the blended mixture to give an extrudate; (c) spheronising the extrudate until spheroids are formed; (d) drying the spheroids; and (e) formulating the spheroids to give the composition, said composition having an in vitro dissolution rate of at least 90% in 45 minutes Preferably the spheroids are dried until the moisture content is 7%. by weight or less of the total spheroid weight as measured by Karl Fischer titration. Conveniently after drying the spheroids are sieved to give spheroids having a predetermined particle size range. Compositions according to the present invention are conveniently formulated for oral administration in unit dosage form in conventional manner. A unit dose may consist of, for example, a capsule, sachet or cachet containing a predetermined quantity of the spheroids. It will be appreciated that the quantity is determined by the dose of active ingredient to be incorporated in a unit dose of the composition. Preferred doses will be well known to those skilled in the art. Compositions in the form of a capsule or cachet may be administered directly via the oral route. A capsule or sachet may conveniently be sprinkled onto food to be taken as part of a meal. In order that the invention may be well understood the following examples are given by way of illustration only. Example 1 Capsules having the following formulation were prepared; mg Hydromorphone hydrochloride 1.3 Microcrystalline cellulose Avicel pH 101 39.35 Lactose, anhydrous 39.35 Purified Water q.s. Fill Weight 80 Hydromorphone hydrochloride (1.3mg), microcrystalline cellulose (39.35mg) and lactose (39.35mg) were dry mixed. Water was added to from a granular mass which was then extruded to form a uniform, free flowing extrudate. The extrudate was spheronised and the resultant spheroids dried until they had a moisture content of about 7 by weight. The dried spheroids were sieved to obtain the 0.85-1.4mm sieve fraction. Example 2 The procedure of Example 1 was followed except that the amount of hydromorphone hydrochloride was increased to 2.6mg and that of microcrystalline cellulose and lactose to 78.7mg. The fill weight was 160mg. Comparative Following the procedure of Example 1 a composition having the following formulation was prepared; mg Hydromorphone hydrochloride 1.3 Microcrystalline cellulose Avicel pH 101 77.0 Hydroxypropylmethylcellulose, E15 1.7 Purified Water q.s. Fill Weight 80 The water soluble binder, hydroxypropylmethylcellulose, was included in the formulation to ensure that spheroids were produced with a low friability. In vitro dissolution studies In vitro dissolution studies were conducted on compositions prepared as described in Examples 1-2 and the comparative example. The dissolution method was by Ph. Eur. paddle apparatus operated at 50rpm with distilled water at 37°C as dissolution media. Results are given in Table 1. Table 1 also gives the results obtained with a marketed normal release hydromorphone hydrochloride tablet (DILAUDID, trade mark). Time (mins) wt% Hydromorphone released Ex 1 Ex 2 Comparative Dilaudid 10 79.7 83.3 52.7 59.4 20 90.5 93.3 69.2 88.6 30 90.7 96.7 73.3 100.8 45 93.6 99.1 77.9 103.1 60 94.0 101.2 85.7 103.1

Claims: A normal release pharmaceutical composition comprising spheroids comprising microcrystalline cellulose, a sugar and a pharmaceutically acceptable salt of hydromorphone having a water solubility of 1 part solute by weight in 30 parts or less of solvent, the composition having an in vitro dissolution rate of the salt of at least 90% in 45 minutes. A composition according to Claim 1 wherein the active ingredient is present in an amount from 0.1% to 25% by weight. A composition according to Claim 1 or Claim 2 wherein the microcrystalline cellulose is present in an amount from 25% to 75% by weight. A composition according to any one of Claims 1 to 3 wherein the sugar is present in an amount from 25% to 75% by weight. A composition according to any one of Claims 1 to 4 wherein the ratio of microcrystalline cellulose to sugar is between 1:3 and 3:1 by weight. A composition according to any one of Claims 1 to 5 wherein the active ingredient comprises hydromorphone hydrochloride. A composition according to any one of claims 1 to 6 wherein the sugar comprises lactose. A composition according to Claim 1 comprising spheroids comprising from 1.0% to 5.0% by weight hydromorphone hydrochloride, from 25% to 75% by weight microcrystalline cellulose and from 40% to 60% by weight lactose. A composition according to any one of Claims 1 to 8 adapted for oral administration. A process for preparing a composition according to Claim 1 comprising the steps of (a) blending a mixture comprising microcrystalline cellulose, a sugar and a pharmaceutically acceptable salt of hydromorphone having a water solubility of 1 part solute by weight in 30 parts or less of solvent; (b) extruding the blended mixture to give an extrudate; (c) spheronising the extrudate until spheroids are formed; (d) drying the spheroids; and (e) formulating the spheroids to give the composition, said composition having an in vitro dissolution rate of at least 90% in 45 minutes

Inventors: KNOTT TREVOR JOHN, LESLIE STEWART THOMAS, MALKOWSKA SANDRA THERESE ANTOI, MILLER RONALD BROWN DR, NEALE PHILIP JOHN, PRATER DEREK ALLAN, KNOTT, TREVOR JOHN, LESLIE, STEWART THOMAS, MALKOWSKA, SANDRA THERESE ANTOINETTE, MILLER, RONALD BROWN, DR., NEALE, PHILIP JOHN, PRATER, DEREK ALLAN
Applicants: EURO CELTIQUE SA, EUROCELTIQUE S.A.
Application year: 1993
Main classification: A61K9
IPC codes: A61K47, A61K9, A61K31, A61P25