EP1198228A2

EP1198228A2 - Release of poorly soluble agents

Info

Publication number: EP1198228A2
Application number: EP00935270A
Authority: EP
Inventors: Charles Tokunbo Adesuyi; Mark Alexander Livingstone; David Montieth; Gordon Findlay Dawson
Original assignee: Cenes Drug Delivery Ltd
Current assignee: Cenes Drug Delivery Ltd
Priority date: 1999-05-19
Filing date: 2000-05-18
Publication date: 2002-04-24
Also published as: CA2374051A1; AU5082700A; JP2003500347A; GB9911546D0; WO2000071095A3; WO2000071095A2

Abstract

A controlled release pellet for releasing a poorly soluble active agent comprises a core containing the active agent (e.g. nifedipine, glibenclamide, griseofulvin, oxaprozin, ibuprofen, diclofenac, nabumetone etc.), a polyethylene glycol and a carrier; the core having a coating comprising a water soluble cellulose and a water insoluble acrylic polymer. A disintegrating agent is preferably included in the core.

Description

RELEASE OF POORLY SOLUBLE AGENTS The present invention relates to a controlled release pellet composition for delivering a poorly soluble pharmaceutically active agent in a controlled manner over an extended period of time, typically over a period of 24 hours. The formulation is intended to enhance and control the release rate of agents, such as nifedipine, which are otherwise only poorly soluble in aqueous liquids.

Enhancement of the rate of dissolution of nifedipine has been the subject of research. Shu-Yang Yen et al (Drug Development and Industrial Pharmacy, 23(3), 313-317 (1997)) report that dissolution enhancement of nifedipine may be achieved by using super-disintegrants such as sodium starch glycolate, crospovidone and croscarmellose sodium. Nifedipine was formed into uncoated granules and tablets. Substantial dissolution was achieved within about 60 minutes. However, there is no report on the controlled release properties of these formulations.

Chowdray KPR and G. Girija Sankar (Drug Development and Industrial Pharmacy 23(3), 325-330 (1997)) describe the icroencapsulation of nifedipine with Eudragit RL PM (a water-insoluble acrylic polymer) . The core contained in addition to nifedipine, hydroxypropylmethyl cellulose and microcrystalline cellulose. Release of nifedipine over a period of 12 hours was reported.

The bioavailability of cores containing nifedipine and hydroxypropylmethyl cellulose phthalate together with methacrylic acid-methacrylic acid methyl ester copolymer

(Eudragit L) was investigated in animal studies reported in

A. Hasegawa et al (Chem. Pharm. Bull.33(1) 388-391 (1985)).

US Patent 5,051,263 (Barry et al) describes a sustained release granule formulation comprising a core containing a poorly soluble active agent such as nifedipine, the core being coated with a mixture comprising a water insoluble but water swellable acrylic polymer and a water-soluble hydroxylated cellulose derivative. The core comprises the active agent, a carbomer (generic name for carboxypolymethylene) and microcrystalline cellulose.

It is an object of the present invention to provide improved controlled release formulations for use with pharmaceutical agents which are poorly soluble in water.

The present invention is based on the surprising discovery that the incorporation of a polyethylene glycol into the core improves the controlled release properties.

Thus, the present invention provides a controlled release pellet, which comprises:

- a core containing a poorly soluble pharmaceutically active agent and a polyethylene glycol;

- a coating around the core and comprising a water- soluble cellulose and a water-insoluble acrylic polymer.

The invention also relates to a corresponding method of forming the controlled release pellet.

The core may be formed in conventional manner as set out in, for example, patent specifications US 4,900,558, US 5 , 051 , 3 63 and US 5 , 055 , 306 .

The core may also contain a disintegrant such as sodium starch glycolate, crospovidone and croscarmellose sodium. The amount of disintegrant is generally in the region 0-10% by weight, particularly 1-5% by weight.

In addition to the pharmaceutically active agent and the polyethylene glycol, the core generally also comprises a carrier such as a water-insoluble swellable cellulose, such as microcrystalline cellulose. A pH modifier, such as sodium bicarbonate, dibasic calcium phosphate, citric acid or tris(hydroxymethyl) aminomethane (Tris) , may be included in the core to buffer the core to a pH which gives preferred dissolution characteristics for the active agent. This may be used to improve the solubility of certain poorly soluble active agents. Where the pellets are to be formed into tablets, a proportion of a water insoluble or pH sensitive acrylic polymer may also be included in the core to maintain the preferred dissolution rate after compression. The amount of carrier in the core is preferably in the region 0-70% by weight, particularly 10- 60% by weight. The amount of water insoluble acrylic polymer in the core is preferably in the region 0-50% by weight, particularly 10-30% by weight.

Generally, the cores have a size in the range 0.5 to 2.0mm, preferably 0.5 to 1.4mm.

The polyethylene glycol which is included in the core has been found to enhance the dissolution rate of the poorly soluble active agent and also to assist in providing controlled release. Polyethylene glycols are well known in the art and include a repeating -(CH₂CH₂0)- group with various terminal groups. Polyethylene glycols are categorised according to their nominal molecular weight and in the present invention nominal molecular weights of 1000 to 8000 (i.e. PEG 1000 to PEG 8000) are preferred. The polyethylene glycol is generally a solid at room temperature but is melted prior to formulation. Usually, the amount of polyethylene glycol in the core is in the range 5-50% by weight, particularly 10-30% by weight.

The amount of polyethylene glycol required is to an extent dependent on the amount of active agent present and it is preferred that the ratio of polyethylene glycol to active agent lies in the range 0.5 to 2.0:1 by weight.

The poorly soluble pharmaceutically active agent is typically nifedipine or other poorly soluble active agent such as glibenclamide, griseofulvin oxaprozin, ibuprofen, diclofenac, or nabumetone. The active agent is generally present in an amount of 1-90% by weight, typically 5-70% by weight of the core weight. The solubility of the poorly soluble active agent in water is generally less than lmg/iαl at room temperature and pH7. The solubility of nifedipine is less than O.lmg/ l.

The coating around the core controls release of the active agent from the core itself (in conjunction with the properties of the core matrix) . The coating comprises a mixture of a water soluble cellulose and a water insoluble acrylic polymer. The ratio of water insoluble agent to water soluble agent is a factor controlling the release rate and the ratio is generally in the range of 1:1 to 10:1, generally 5:3 to 5:1 respectively. The water insoluble acrylic polymer is preferably neutral and may comprise a homopolymer or copolymer, for instance of acrylic acid esters or methacrylic acid esters. Usually, the acrylic polymer is provided as an aqueous dispersion. A particularly suitable acrylic polymer is sold under the trademark Eudragit NE30D and comprises a copolymer of acrylic and methacrylic acid esters and is usually supplied as an aqueous dispersion containing approximately 30% by weight solids.

The water soluble cellulose may be a hydroxylated cellulose derivative, such as hydroxypropylmethyl cellulose, typically having a degree of substitution of 28- 30% of methoxy groups and 7-12% of hydroxypropyl groups. Hydroxypropyl, hydroxyethyl or hydroxymethyl celluloses may also be used.

The coating preferably comprises from 3-40% by weight, preferably 5-25% by weight of the pellet.

Since active agents such as nifedipine may interact with food in the stomach, in a particularly preferred embodiment the pellet is further coated with an enteric coating. Enteric coatings are well known in the art and typically comprise an acid-resistant agent.

If necessary, the pellets of the present invention may be formed into tablets together with conventional tableting agents . Embodiments of the present invention will now be described by way of example only.

Example 1

Cores containing nifedipine and polyethylene glycol (PEG4000) having the formulations set out in Table 1 were prepared as described below.

Table 1 (Core Formulation)

The cores were coated with two coating suspensions. The first coating suspension functioned as a release rate controlling coat and had the formulation as set out in Table 2. The coating suspension contained 20%w/w solid material and the weight of suspension added was equivalent to 5% of the core weight. Table 2- First Coatinσ Suspension (Release Rate Controlling Coat)

A second (enteric) coating was also applied. The second coating suspension is shown in Table 3 and contained 20%w/w solid material. The weight of suspension added was equivalent to 10% of the core weight.

Table 3 - Second Coating Suspension (Enteric Coat)

(a) Core Production

A 1kg batch of cores (batch 5507:00198) was produced as follows. Molten PEG4000 was weighed into a pre-heated mixing bowl of a Erweka AR401 planetary mixer at a temperature of 90°C. Nifedipine was added over a period of 1 to 2 minutes at a mixing speed of approximately I80rpm and the mixture mixed for a further 2 to 3 minutes . Ac-Di- Sol was dispersed in the batch quantity of water and added to the nifedipine/PEG4000 mixture over 4 minutes at lOOrpm. Avicel PH101 was added and mixed over a period of 7 to 8 minutes at lOOrpm to produce a wet mass. The wet mass was covered and allowed to cool for approximately 30 mins to 29°C. Then the wet mass was extruded through a 0.8mm screen of a Niro Fielder E140 extruder at a feeder speed of approximately 45rpm and an impeller speed of approximately 30rpm. The extrudate was collected and spheronised for 12.5 minutes in a Niro Fielder S450 spheroniser at approximately 400rpm. The spheres were collected and dried at approximately 55°C in an Aeromatic Fielder Strea 1 fluid bed drier. The dried cores were sieved to between 0.5 and 1.4mm to remove fines and large agglomerates.

b) Coated Pellet Production

A batch size of 600g of the cores was coated to produce pellets (batch 5509:00198) as follows. The first coating suspension was prepared by dissolving hydroxypropylmethyl cellulose (Pharmacoat 603) in approximately 450g of purified water and mixing with a low shear mixer for approximately 2 hours . Talc was added and dispersed using a Silverson SL2 hi-shear mixer for approximately 30 mins. This mixture was added to the Eudragit NE30D, made up to lOOOg with the remaining purified water and stirred for 20 minutes at approximately 350rpm using a Heidolph RZR2051 mixer until uniform.

The second coating suspension was prepared by dispersing the triethyl citrate and talc in approximately 300g of purified water using a Silverson SL2 hi-shear mixer for 7 minutes, adding to Eudragit L30D-55 and the remaining water and stirring at approximately 350rpm for 6 minutes using a Heidolph RZR2051 mixer until uniform.

The first coating suspension was added to the batch of cores in an Aeromatic Fielder Strea 1 fluid bed drier using a 0.8mm spray gun nozzle at 8g/min (1 bar atomising pressure, inlet temperature 35 °C and airflow of 90m³/hr) to form a first coat. The second coating suspension was added immediately thereafter using a 1. lmm spray gun nozzle at approximately llg/min (1 bar atomising pressure, inlet temperature 35 °C and airflow of approximately 100m³/hr) to form a second coat. The coated cores were placed in an LTE Vulcan 150 oven to cure at approximately 45°C for approximately 20 hours. The coated cores were sieved through a 1.4mm screen to remove agglomerates. The pellets so produced were then stored.

(c) Release Profiles

Figure 1 shows the release profile of the coated core of the invention in 900ml of a dissolution medium containing 1% sodium lauryl sulphate and 1% propanediol in simulated gastric fluid (37°C and lOOrpm. stirring) . It will be noted that there is good controlled release over the 24 hour period shown. Example 2 (Comparison)

For comparison purposes, four batches of uncoated nifedipine-containing cores were prepared as in Example 1 having the composition set out in Table 4.

Table 4 (uncoated cores)

The formulation DNIF97/041 is substantially the same as the uncoated core of Example 1.

Figure 2 shows the release profiles in vitro (determined as in Example 1) . It can be seen that the presence of both the polyethylene glycol and the croscarmellose sodium (Ac-Di-Sol) enhance the release rate of nifedipine. Both of these additives are preferred to provide a sufficiently fast dissolution rate of the uncoated pellet cores such that control can be exercised over the final release rate by addition of a rate controlling coating. Example 3

Uncoated Oxaprozin containing cores were manufactured as detailed in Example 1. The composition of these uncoated cores is summarised in Table 5.

Pellets were sieved to between 0.5 and 1.4mm and further processed by coating with a suspension in order to produce a release rate controlling membrane. The composition of the coating suspension applied is detailed in Table 6. The coating suspension contained 20% w/w solid material and the weight of suspension applied was equivalent to 25% of the initial core weight.

Oxaprozin release was studied in-vitro in 0.05M KH₂P0₄ buffer (pH 8.0, 37°C, lOOrpm). Samples were taken manually and Oxaprozin determined by HPLC (Acetonitrile: H₂0 45:55 with 2.5ml/L Acetic acid; Nucleosil ODS lOμm 250 x 4.6mm, flow rate - 1.5ml/min; 250nm) . The resulting release profiles are summarised on Figure 3. It will be noted that the effect of polyethylene glycol and Ac-di-sol follows broadly the same trend as seen in Example 2. That is to say that the rate of release is increased in the presence of Ac-di-sol and further by the presence of PEG and Ac-di- sol. However, PEG alone has only a small effect in this case.

Example 4

Uncoated Ibuprofen containing cores were manufactured as detailed in Example 1. The composition of these uncoated cores is detailed in Table 7.

Pellets were sieved to between 0.5mm-1.4mm and further processed by coating with a suspension to produce a release rate controlling membrane. The composition of this suspension is detailed in Table 8. The coating suspension contained 20% w/w solid material and the weight of suspension applied was equivalent to 12% of the initial core weight.

Ibuprofen release was studied in-vitro in 0.05M KH₂P04 (pH 6.8, 0.05M, 30°C, lOOrpm). Ibuprofen was determined spectrophotometrically (264nm) . The resulting release profiles are summarised in Figure 4. It will be noted that the effect of polyethylene glycol and Ac-di-sol follows the same trend as seen in Example 2. That is to say that the rate of release is increased in the presence of PEG, is increased still further by Ac-di-sol and is greatest in the presence of both PEG and Ac-di-sol. Example 5

Uncoated Diclofenac sodium containing cores were manufactured as detailed in Example 1. The composition of these cores is detailed in Table 9.

Pellets were sieved to between 0.5mm-1.4mm and further processed by coating with a suspension to form a release rate controlling membrane. The composition of this suspension is detailed in Table 10. The coating suspension contained 20% w/w solid material and the weight of suspension added was equivalent to 25% of core weight.

Diclofenac release was studied in-vitro in 0.05M KH₂P0₄ buffer (pH 6.8, 37°C and lOOrpm). Samples were taken Diclofenac release was studied in-vitro in 0.05M KH₂P0₄ buffer (pH 6.8, 37°C and lOOrpm). Samples were taken manually and Diclofenac determined spectrophotometrically (248nm) . The resulting release profiles are summarised in Figure 5. It will be noted that the effect of polyethylene glycol and Ac-di-sol follows the same trend as seen in Example 2. That is to say that the rate of release is increased in the presence of PEG, is increased still further by Ac-di-sol and is greatest in the presence of both PEG and Ac-di-sol.

Example 6 (Various PEG's)

Uncoated Diclofenac Sodium containing cores were manufactured as detailed in Example 1. These cores contained PEG 6000 which replaced the PEG 4000 used in Example 5. The formulation of the uncoated cores is detailed in Table 11.

Pellets were sieved to between 0.5mm - 1.4mm and coated with a suspension to form a release rate controlling membrane. The composition of this suspension is summarised in Table 12. The suspension contained 20% solid material and the weight of suspension added was equivalent to 25% of core weight.

Diclofenac release was studied in-vitro in 0.05M KH₂P0 buffer (pH 6.8, 37°C and lOOrpm). Samples were taken manually and Diclofenac determined spectrophotometrically (248nm) . The resulting release profiles are summarised in Figure 6. The effect of PEG 6000 is similar to that of PEG 4000. This can be seen from the superimposition of the profiles obtained from pellets containing these two components. Furthermore the effect of PEG 4000 and 6000 is potentiated in the presence of Ac-di-sol in line with other examples. Example 7

Uncoated Glibenclamide containing cores were manufactured as detailed in Example 1. The formulation of the uncoated cores is detailed in Table 11.

Pellets were sieved to between 0.5mm-1.4mm and further processed by coating with a suspension to form a release rate controlling membrane. The composition of this suspension is detailed in Table 14. The coating suspension contained 20% w/w solid material and the weight of suspension applied was equivalent to 25% of core weight.

Glibenclamide release was studied in 0.01M NaOH ( 37°C, lOOrpm) . Glibenclamide was determined spectrophotometrically (229nm) . The resulting release profiles are summarised in Figure 7. It will be noted that the effect of polyethylene glycol and Ac-di-sol follows the same trend as seen in Example 2. That is to say that the rate of release is increased in the presence of PEG, is increased still further by Ac-di-sol and is greatest in the presence of both PEG and Ac-di-sol.

The following are trademarks: Avicel, Ac-Di-Sol, Eudragit and Pharmacoat.

Claims

1. A controlled release pellet, which comprises:

- a core containing a poorly soluble pharmaceutically active agent and a polyethylene glycol; a coating around the core and comprising a water soluble cellulose and a water insoluble acrylic polymer.

2. A pellet according to claim 1, wherein the core further contains a disintegrant.

3. A pellet according to claim 2, wherein the disintegrant is croscarmellose sodium.

4. A pellet according to claim 2, wherein the disintegrant is sodium starch glycolate or crospovidone.

5. A pellet according to any of claims 2 and 4, wherein the disintegrant is present in an amount of 1 to 5% by weight of the core.

6. A pellet according to any preceding claim which further contains a carrier which is a water-insoluble swellable cellulose.

7. A pellet according to claim 6, wherein the carrier is present in an amount of 10 to 60% by weight of the core.

8. A pellet according to any preceding claim wherein the polyethylene glycol has a nominal molecular weight of 1000 to 8000.

9. A pellet according to claim 8 wherein the polyethylene glycol is present in an amount of 5 to 50% by weight of the core.

10. A pellet according to claim 9 wherein the polyethylene glycol is present in an amount of 10 to 30% by weight of the core.

11. A pellet according to any preceding claim wherein the ratio of polyethylene glycol to active agent is in the range 0.5 to 2.0:1 by weight.

12. A pellet according to any preceding claim wherein the active agent is nifedipine, glibenclamide, griseofulvin, oxaprozin, ibuprofen, diclofenac or nabumetone.

13. A pellet according to claim 12 wherein the active agent is present in an amount of 5 to 70% by weight of the core.

14. A pellet according to any preceding claim wherein the active agent has a solubility in water of less than lmg/ml at room temperature and pH7.

15. A pellet according to any preceding claim wherein the ratio of water insoluble acrylic polymer to water soluble cellulose in the coating is in the range 1:1 to 10:1 respectively.

16. A pellet according to any preceding claim wherein the coating comprises 3 to 40% by weight of the pellet.