WO1995017171A1

WO1995017171A1 - Delivery device for delayed release of an active containing a solubilising agent

Info

Publication number: WO1995017171A1
Application number: PCT/GB1994/002792
Authority: WO
Inventors: Massoud Bakhshaee; Howard Norman Ernest Stevens
Original assignee: R.P. Scherer Corporation
Priority date: 1993-12-23
Filing date: 1994-12-22
Publication date: 1995-06-29
Also published as: GB9326266D0

Abstract

A delivery device for delivering an active substance after a predetermined time delay (e.g. 0.5 to 12 hrs) after administration to a patient, comprises a hollow female body (2) having a plug (6) formed of a hydrogel material in the neck (4) thereof. The plug swells in contact with an aqueous medium (e.g. gastronintestinal fluid) and disengages at the predetermined time. The active material (12) is mixed together with a solubilising agent, such as a sugar or a wetting agent, which enhances the delivery of the active material from the device into the aqueous medium after disengagement of the plug.

Description

Delivery device for delayed release of an active containing a solubiUsing agent

TECHNICAL FIELD

The present invention relates to a controlled release device (e.g. a capsule) for delivering a pharmaceutically active material, which comprises a male member engaged within a neck portion of a female body; the device including a water-swellable material which swells so as to disengage the female body upon exposure to an aqueous medium. In particular, it relates to the presentation or formulation of the active material such as to enhance delivery of the active material from within the body promptly once the male member has become disengaged.

BACKGROUND

International patent specification W090/09168 discloses a device of this type which comprises a water-swellable male plug engaged within a female body. A pharmaceutically active material is contained within the device. When the device is exposed to water, the male hydrogel plug swells and eventually disengages itself from the female body, thereby allowing the pharmaceutically active material contained within the device to be released. It has been found that the time taken to disengage the plug (e.g. 0.5 to 12 hours) is reasonably predictable, so that the device may be used to release pharmaceutically active materials within the body of a patient after a predetermined time interval. This may, for example, be useful in the treatment of medical conditions where it is desirable to administer a pharmaceutically active material to a patient sometime through the night while the patient is asleep, so as to provide a desired level of the drug in the patient in accordance with his needs during the night or when he awakes. It may also be useful to allow dosing of materials at a predetermined point as the capsule passes through the gastro-intestinal tract, for example in the colon.

Patent specification W092/13521 (Alza Corporation) describes fluid-imbibing dispensing devices for delayed delivery of an active agent, which include an expansion means which absorbs fluid from a surrounding environment. The dispensing device comprises a housing having first and second wall sections telescopically engaged with each other, particularly a capsule having a hollow cap and a hollow body; either the cap or the body is in the form of a male section fitted inside the open end of the other female section. The expansion means is contained within the device and expands as it absorbs fluid, forcing apart the two sections of the device. The expansion means may be a swellable polymer or an osmotic formulation which swells as it absorbs fluid. In order to allow fluid to come into contact with the expansion means contained within the device, one of the wall sections adjacent to the expansion means is fluid-permeable. After the sections are disengaged, fluid enters the device and comes into contact with the active agent contained within the device, thereby dispensing the active agent into the fluid.

Whilst it has been found that the time to disengagement of the male member may be arranged to be reproducible, difficulties may be encountered with ensuring complete emptying of the active material from within the female body. This arises due to the limited access of the aqueous medium to the active material within the body, and the problem tends to be compounded as the solubility of the active material decreases. Furthermore, it may be desirable to arrange for release of the active material to take place lower down in the gastro-intestinal tract, e.g. in the colon, where the intestinal water content is relatively low.

It is an object of the present invention to enhance the emptying of the active material from within the body of the device.

SUMMARY OF THE INVENTION

The present invention provides a controlled release device for delivering an active material, which comprises a male member engaged within a neck portion of a female body; the device including a water-swellable material which swells so as to disengage the female body upon exposure of the device to an aqueous medium; the female body containing the active material together with a solubilising agent which enhances the delivery of the active material from the device.

Thus according to the invention, the use of the solubilising agent enhances the delivery of the active material. The solubilising agent may directly assist dissolving of the active material in aqueous medium present in the gastro-intestinal tract of the patient. Alternatively, the solubilising agent may assist the transport of the undissolved active material from the device into the patient's gastro-intestinal tract, thereby dispersing the active material in the aqueous medium outside the device. For example, the solubilising agent may form a syrup which flows from the device and carries the active material with it.

Generally, the active material is formulated as a solid formulation, but may also be formulated in a liquid form. Preferred solid formulations include granules, pellets and tablets. In the case of solid forms, the solubilising agent may have the effect of causing the solid to disintegrate thus improving the rate of dissolution. Preferably, the active material is granulated into particles having a size 100-1000 microns.

The active material may be uniformly distributed throughout the solid form. Alternatively, the active material may be applied as an outer layer onto a core formed of the solubilising agent.

In another embodiment, the solubilising agent is present as a discrete layer within the female body, the active material being present as a separate layer on top of the solubilising agent, so as to be closer to a mouth of the female body. In use, aqueous medium enters the body after disengagement of the male member and the solubilising agent dissolves therein. The solution or syrup so formed tends to flow out of the body, particularly as the device moves within the gastro-intestinal tract of the patient, carrying with it the active material. The effect is to assist delivery of the active material from the body of the device into the gastro-intestinal tract of the patient.

The solubilising agent is one which generally speaking has a solubility in the aqueous medium which is greater than the solubility of the active material. However, solubilising agents of lower solubility may also be used. The solubilising agent should, of course, be pharmaceutically acceptable. Preferred solubilising agents include sugars, (monosaccharides or polysaccharides) , such as glucose, sorbitol, sucrose, mannitol, xylitol, dextrose and lactose.

In order to assist wetting, a wetting agent may be included in the solubilising agent, such as any pharmaceutically acceptable wetting agent, e.g. sodium docusate (available under the tradename Alcopol) , sodium lauryl sulphate, a Tween (e.g. Tween 20 or 80) , Crill 1, or Crill 4. The walls of the female body may be formed from a wide variety of materials. They may be of homogenous constructions or they may be laminated. Examples of materials suitable for use in the construction of the body include polyethylene, polypropylene, poly(methylmethacrylate) , polyvinyl chloride, polystyrene, polyurethanes, polytetrafluoroethylene, nylons, polyformaldehydes, polyesters, cellulose acetate and nitro cellulose.

However, a preferred construction uses an impermeable coating to cover the exterior of a capsule formed from a water-soluble material. The coating may conveniently be formed by dipping a capsule body in a solution of a material which forms a layer which is impermeable to water. Alternatively, the body may be spray-coated. A preferred class of capsules are conventional hard gelatin or starch capsules coated with a solution of polyvinyl chloride or a polyvinyl acetate copolymer, or an ethyl cellulose solution.

In a preferred embodiment, the male member is a plug formed of said water-swellable material, such that as the plug swells it disengages from the female body. The plug is preferably formed of a water-swellable hydrogel, such as described in W090/09168.

Preferred hydrogel materials are mentioned in W090/09168 and include poly(hydroxyethyl- ethacrylate) , poly(N-vinyl-pyrrolidone) , and polyurethanes. A particularly preferred class of hydrogels are those cross-linked hydrophilic polymers comprising polyethylene oxide residues. Chemical cross-linking may be effected in known manner. Where the hydrophilic polymer comprises functional groups which comprise an active hydrogen atom, chemical cross-linking may be effected by means of di-or-polyisocyanates. Preferably, the polyethylene oxide residues have a number average molecular weight greater than 1500, preferably greater than 3,000, and most preferably from 4,000 to 12,000. Particularly preferred polyurethane materials are formed by polymerising a polyethylene glycol, with a

alkanetriol, and a diisocyanate.

Preferably, the water swellable material has a swelling capacity of greater than 50%, particularly greater than 100%, preferably greater than 200% and advantageously more than 300%. This percentage swellability represents the percentage increase in weight over and above the original weight.

Preferably, the controlled release device is in the form of a capsule, provided with a cap formed of a water-soluble material such as a hard gelatin cap, which dissolves as soon as the capsule enters the patient's stomach.

In another embodiment, the male member is a hollow member closed at one end, whose opposite open end engages within the neck of the female body. A water swellable material is provided within the device which serves to disengage the female member after a predetermined time, by forcing the male member and the female body apart as the material swells in the presence of water. The swellable material inside the device may be an osmagent or an osmopolyer. Such an arrangement is disclosed in W092/13521. In order to allow water to enter the device and to contact the water-swellable material a portion of the wall of the device adjacent thereto is preferably semipermeable; that is to say it is permeable to the passage of water into the device but impermeable to release of other substances from within the device.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Embodiments of the present invention will now be described by way of example only and with reference to the figure wherein;

Figure 1 shows a cross section through a capsule to an enlarged scale. This comprises a capsule body 2 in the form of a hard gelatin body and coated with a water-impermeable coating. The capsule body is formed in conventional manner by dipping a mould pin into a gelatin solution and allowing to dry. The gelatin is then coated with a water-impermeable coating (e.g. by dip coating) after the capsule body has been stripped from the mould pin and trimmed to size. Alternatively, the water-impermeable coating may be applied by spray coating or vapour deposition.

The capsule body includes a cylindrical neck portion 4.

A male plug 6 formed of a hydrogel material is inserted into the neck portion. A preferred hydrogel composition is given in Example 1. The plug may be flush with or proud of mouth 10 of the body, or may be recessed below the mouth as shown.

The degree of recessing is a factor in determining the plug disengagement time.

The capsule is sealed with a cap 8, formed of a water-soluble material, such as a hard gelatin cap.

The body contains a fill 12 is in the form of granules in which the active material has been homogenously mixed with excipients and granulated. Alternatively, the active agent may be layered on the outside of the granules.

When the capsule is administered to a patient, the aqueous environment in the gastro-intestinal tract quickly dissolves the water-soluble cap 8. Water is then absorbed into the hydrogel plug 6, which swells and is expelled from the body after a predetermined time interval (for example 2 to 10 hours) referred to as the "pulse" time. This allows access of the aqueous medium within the gastro-intestinal tract to the contents of the capsule body. The soluble solubilising agent dissolves quickly in the aσueous medium, causing the granules to disintegrate and to disperse the active material (which may be more or less soluble than the solubilising agent) . This assists dissolution of the active material and also flushing of the active material from the interior of the capsule body.

EXAMPLE 1 (Hydrogel production)

Hydrogel rods were prepared by polymerising 6,000 grams of polyethylene glycol PEG 8000 (Pharma) of number molecular weight Mn 8700 and ratio Mw/Mn = 1.03 (where Mw is the mean molecular weight) with 111.04 grams of hexanetriol, 506.8 grams of Desmodur W

(dicyclohexylmethane-4,4-diisocyanate) , and catalysed by 0.6 grams of anhydrous ferric chloride. The mole ratios were PEG 8000 (1 mole), hexanetriol (1.2 moles), Desmodur W (2.8 moles) and ferric chloride (0.01% by weight of PEG) . The PEG 8000 was melted and dried to less than 0.05% w/w moisture content in a Buchi Rotavapor at 95° C, at a pressure less than 5 millibars for a period of two hours. Then, the ferric chloride was dissolved in the hexanetriol at 75°C, and the mixture stirred into the dried PEG for 5 minutes at 100 rpm. The mixture at 85°C was then mixed with the Desmodur W by pumping into a mixer rotating at 1500 revolutions per minute. Molten polymer at about 80°C was then dispensed into tubuler polytetrafluorethylene moulds 25cm long and internal diameter about 6.7mm under a vacuum of less than 50 millibars. Curing took place at 95°C for 4 hours in a fan equipped oven. The hydrogel polymer rods were then allowed to cool.

The hydrogel rods are washed by immersion in a circulating stream of water containing butylated hydroxy anisole (BHA) as a stabiliser. The washing removed water-soluble extractable substance from the polymer and the BHA stabiliser becomes incorporated into the polyer.

The swelling factor is defined as (Ws-Wd)/Wd x 100, where Ws is the swollen weight and Wd is the dry weight. The hydrogels were found to have a swelling factor of 270± 25.

EXAMPLE 2

A pharmaceutically active material was mixed with sucrose (35.8 grams). Sodium docusate (0.448 grams), was dissolved in isopropanol as solvent, then the mixture was added to the solution and mixed thoroughly. The solvent was then driven off and the mixture granulated. The mean particle size of the granules was 600 microns.

A coated gelatin capsule body was then filled with sucrose, and a layer of the granulated mixture placed on top. The capsule was then sealed with a hydrogel plug. The plug had a nominal length 3.5mm, nominal diameter 6.9mm, and was recessed 0.5mm below the mouth of the capsule body.

The weight of the capsule was approximately 106mg, the weight of sucrose fill was approximately 420mg, and the weight of granulated mixture was approximately 50mg.

In order to measure the delivery time of the active material, the capsule was placed in one litre of double distilled water at 37°C stirred at 50rpm. Release of the active material was monitored spectrophotometrically.

For six capsules, the delivery times ranged from 4.0 to 4.75 hours (mean 4.29hrs, standard deviation 0.2). The standard deviation indicates good reproducibility of delivery time. As regards completeness of emptying of the capsule, on average 95.6% of the drug had been released by one hour after disengagement of the plug.

EXAMPLE 3

The procedure of Example 2 was repeated using a capsule having a plug of nominal length 4.0mm, nominal diameter 6.90mm, which was recessed 0.6mm below the mouth of the body. This provided a nominal pulse time of six hours.

The results of six capsules showed a range of delivery times 5.50 to 6.50hrs (mean 5.92hrs, standard deviation 0.4). On average 96.2% of drug was released from the capsule at one hour following disengagement of the plug.

The capsule weight was about 105mg, the weight of sucrose fill was approximately 400mg and the weight of granulated mixture was about 50mg per capsule.

EXAMPLE 4

A fill formulation comprising salbutamol sulphate, was added on top of a sorbitol and sodium docusate powder bed, as follows.

Sodium docusate (0.1 grams) was dissolved in isopropanol solvent. Sorbitol (20 g) was added to the solution and mixed thoroughly. The mixture was dried and granulated to a fine powder. Approximately 216mg of the granulated sorbitol/sodium docusate mixture was filled into a capsule body. Approximately 10 mg salbutamol sulphate was then added on top of this fill.

The hydrogel plug had a length about 4.0mm, a diameter about 6.90mm and was recessed 0.57mm below the mouth of the body. This provided a nominal release time of 5 hours. The release of the salbutimol sulphate was monitored spectrophotometrically. The results showed a range of delivery times 5.00 to 5.25 hrs. (mean = 5.25hrs, standard deviation 0.1).

Claims

1. A controlled release device for delivering an active material, which comprises a male member (6) engaged within a neck portion (4) of a female body (2) ; the device including a water swellable material which swells so as to disengage the female body upon exposure of the device to an aqueous medium; the female body containing the active material (12) together with a solubilising agent which enhances the delivery of the active material from the device.

2. A device according to claim 1 wherein the solubilising agent is intimately admixed with the active material.

3. A device according to claim 1 wherein the active material is in a solid form, and the solubilising agent is present as a coating thereon.

4. A device according to claim 1 wherein the solubilising agent is present as a layer within the female body, the active material being present as a separate layer thereon, so as to be closer to a mouth of the female body.

5. A device according to any preceding claim wherein the solubilising agent comprises a pharmaceutically acceptable monosaccharide or polysaccharide.

6. A device according to any preceding claim wherein the solubilising agent comprises a wetting agent.

7. A device according to any preceding claim wherein the solubilising agent is more soluble in the aqueous medium than the active material.

8. A device according to any preceding claim wherein the male member (6) is a plug formed of said water swellable material.

9. A device according to claim 8 wherein the water swellable material is a hydrogel.