WO1995017173A1 - Drug expelled from oral delivery device by gas - Google Patents

Abstract

A delivery device for delivering an active substance (10) after a predetermined time delay (e.g. 0.5 to 12 hrs) after administration to a patient, comprises a hollow female body (6) having a plug (2) formed of a hydrogel material in the neck thereof. The plug swells in contact with an aqueous medium (e.g. gastrointestinal fluid) and disengages at the predetermined time. An excipient (12) whose volume expands in contact with the aqueous medium is provided in the body to quickly and completely expel the active substance from the body into the aqueous medium after disengagement of the plug. The expandible excipient is a material which generates a gas in contact with aqueous medium, such as a mixture of a carbonate or bicarbonate and an acid.

Description

Drug expelled from oral delivery device by gas

TECHNICAL FIELD

The present invention relates to the expulsion of a substance to be delivered, for example a pharmaceutically active material, from a hollow body of a delivery device, such as a capsule. Particularly though not exclusively, the present invention relates to a controlled release device for delivering the substance to a patient at a chosen time (e.g. 2 to 10 hours) following administration.

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 material within the gastro-intestinal tract 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 pharmaceutically active material to the patient some time 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. Thus, the device is useful to allow administration of active material at a predetermined point as the capsule passes through the gastro-intestinal tract, for example in the colon.

Patent specification 092/13521 (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.

The success of the device depends not only on the release of the male member at the chosen time, but also on the successful emptying of the contents of the capsule shortly thereafter, so that they become absorbed into the patient's system at the required time. The emptying of the capsule requires either an active material which is very soluble in water or an adequate supply of aqueous medium in order to flush the contents from the capsule. However, in lower regions of the gastro-intestinal tract, such as the colon, the water content is low, so that emptying of the capsule may be inhibited.

It is an object of the present invention to address this problem.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a delivery device for delivering a substance, which comprises a hollow body containing the substance to be delivered, together with an excipient whose volume expands in contact with an aqueous environment such as to expel the substance from the body.

Thus, the expansion of the excipient acts to positively expel the substance from the body, such as to provide reproducible delivery times. Preferably, the excipient is a material which generates a gas when it comes into contact with the aqueous medium. Suitable systems are known in the art, and generally comprise a first component in the form of a pharmaceutically acceptable carbonate or bicarbonate, together with a second component in the form of a pharmaceutically acceptable acid. The acid is usually an organic acid in solid form, such as citric acid or adipic acid. The first and second components together constitute an effervescent mixture. In the presence of water, at least the acid dissolves and comes into contact with the carbonate or bicarbonate, thereby releasing carbon dioxide.

In a preferred construction, the device further comprises a male member engaged with a neck portion of the (female) body, the device including a water-swellable material which swells so as to disengage the female body upon exposure of the device to the aqueous medium, and thereby allows the aqueous medium to come into contact with the expandible excipient within the female body.

In one embodiment, the male member is in the form of a male plug formed of the water-swellable material, preferably a hydrogel, engaged within the neck of the female body. The construction, chemical composition and fitting of the male hydrogel plug determines the time taken for the hydrogel plug to swell and become disengaged from the female hollow body (i.e. the "pulse" time) .

Preferred hydrogel materials are mentioned in W090J09168 and include poly(hydroxyethyl-methacrylate) , 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 Cg-C₁₀ alkanetriol, and a diisocyanate.

Preferably, the water-swellable hydrogel 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.

The walls of the female body may be formed from a wide variety of materials, such as disclosed in W090/09168. 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 a water-impermeable coating to cover the exterior of a body formed from a water soluble material. The coating may conveniently be formed by dipping a 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 bodies are conventional hard gelatin or starch capsule bodies coated with a solution of polyvinyl chloride or polyvinyl acetate copolymer, or an ethyl cellulose solution.

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. - 1 -

It has been found that the effervescent mixture in the hollow body may be sensitive to the presence of water vapour, which is a problem particularly where the body may have some limited permeability to water vapour, such as in the case of coated hard gelatin capsules. This may lead to premature gas generation before the substance is intended to be expelled. To avoid this, it is preferred to coat one or both of the components of the effervescent mixture with a water-vapour impermeable coating, for example a hydrophobic coating, such as a wax. Suitable waxes include food grade materials, such as Cutina Suppocire and cetyl ester wax. To assist the coating process, one or both of the components of the effervescent mixture may be granulated or pelleted. Furthermore, the coated effervescent mixture itself may be formed into a tablet.

In a particularly preferred embodiment, the coating material is a material which is solid at ambient temperature but which melts at body temperature of 37°C. Thus, the wax Suppocire AP has a melting point of approximately 34°C, which is below body temperature. However, it has been found that if a water-soluble emulsifying agent is included in the coating formulation, higher melting point waxes can be also employed, such as cetyl ester wax (melting point 43° to 45°C) and hydrogenated castor oil waxes (e.g. Cutina HR, melting point 85 to 88°C) . The water-soluble emulsifying agent is for example sodium docusate (available under the trade name Alcopol) .

In addition, the coating formulation could include a wetting agent, such as sodium stearate, sodium lauryl sulphate, dioctyl sodium sulphosuccinate, a Tween surfactant, a poloxamer such as poloxamer 188, and glycerol monostearate.

In order to minimise the cohesiveness of the coating due to softening of the wax, sugars may be included in the coating formulation so as to improve flow properties and also to aid wetting. The sugar may for example be sorbitol, lactose or sucrose.

Generally, the coating is applied in an amount of 10-200%, preferably 50-100% by weight of the carbonate or bicarbonate.

In order to carry out a coating process, the coating composition may be dissolved in a solvent. Application to the solid excipient may be by pouring, spraying or pan coating the excipient. The solvent may be a suitable food grade solvent, such as isopropyl alcohol. The solvent is then evaporated off.

An alternative way of preventing premature gas generation involves including an inert water absorbing agent, such as silica gel, in the effervescent formulation in order to absorb any water vapour present.

Problems which may arise due to premature gas generation are as follows. Firstly, premature gas generation may force the male member (e.g. a hydrogel plug) out of the female body too early, thereby leading to reduced and unreliable pulse times and delivery times. Moreover, the male member may be ejected with an unacceptable force. Secondly, premature gas generation may use up the effervescent materials, leading to reduced availability later when the substance is intended to be expelled.

A further aspect of the present invention relates to a method of expelling a substance to be delivered from a hollow body, which comprises providing said substance within the hollow body together with an excipient whose volume expands in contact with an aqueous environment such as to expel the substance.

DESCRIPTION OF PREFERRED EMBODIMENTS

Embodiments of the present invention will now be described by way of example only.

Figure 1 is a cross section to an enlarged scale of a delivery device according to the present invention.

The device is in the form of a capsule comprising a male plug 2 formed of a hydrogel material inserted in neck 4 of female body 6. The device is closed with a cap 8 of water-soluble material.

The male plug 2 is formed of a hydrogel material, such as disclosed in W090/09168. In particular, the hydrogel may be formed of a cross-linked polyurethane formed as described in Example 1. The male plug is usually inserted so that the upper end of the plug is proud of, level with or recessed below the upper end of the neck 4.

The cap 8 is formed of a water-soluble material (e.g. is a hard gelatin cap) , which dissolves quickly in the stomach after administration to a patient. The body 6 is formed of a water-insoluble material, which may be a water-insoluble plastics material such as low density polyethylene, or may be a hard gelatin body coated with a water-impermeable coating (such as disclosed in W090/09168) .

A lower layer 12 of an effervescent mixture is contained within the capsule body 6. Positioned above this, is an upper layer 10 of active material which is to be expelled from the body. The active material may comprise a pharmaceutically acceptable carrier if required.

When the device is administered to a patient, the aqueous medium in the gastro-intestinal tract quickly dissolves the water-soluble cap. Water is then absorbed into the hydrogel plug 2, which swells and is expelled from the body 6 after a predetermined time interval (for example 0.5 to 12 hours) . Thereafter, the aqueous medium within the gastro-intestinal tract enters the capsule body and causes the effervescent mixture to effervesce and release carbon dioxide gas. This foaming mixture expels the contents of the hollow capsule body including the active layer 10 and delivers the contents into the gastro-intestinal tract. In order to allow good control of the delivery time, the time for expulsion of the contents of the body 6 after expulsion of the hydrogel plug is preferably short, for example 2 to 20 minutes, compared to the pulse time for disengagement of the plug.

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 Rσtavapor 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 polymer.

The swelling factor is defined as (Ws-Wd) JWd 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 (Suppocire Coated Effervescent Formulations)

Suppocire AP was dissolved in isopropanol and mixed with sodium carbonate, and dried under vacuum for 24 to 48 hours to form granules. The Suppocire coated sodium bicarbonate was then blended with the other raw materials as set out in Table l below. The Table indicates the emptying time for effervescent formulations placed in open-ended low density polyethylene capsules, after the capsules were placed in a bath containing water and equipped with a stirrer (50 rpm) . TABLE 1 - Effervescent Formulations,

% w/w

1 2 3 4 5 1

|Sodium Bicarbonate 50.00 43.25 58.30 21.60 21.60 |

|Citric Acid 50.00 43.25 22.30 21.60 21.60 |

|Suppocire AP - 13.50 19.40 - |

|Suppocire A - - - 6.80 6.80 |

|Sucrose - - - 50.00 |

|Lactose - - - - 47.50 |

|Alcopol* — — _ — 2.50 |

|Emptying Time

1 (mins) Visual - 4 4 8 2.5 I

* Sodium docusate

EXAMPLE 3 (Cutina Coated Formulations)

Formulations were made up as in Example 2 using Cutina HR as the coating for the sodium bicarbonate. The details and results are given in Table 2 below.

TABLE 2 - Formulations with Cutina HR.

%W/W

1 1 2 3 I

|Sodium Bicarbonate 25.6 25.6 25.6 |

|Cutina HR 2.8 2.8 2.8 |

|Citric Acid 21.6 21.6 21.6 |

|Lactose 47.5 - |

|Alcopol* 2.5 0.5 |

|Sorbitol - 49.5 1

|Sucrose - - 49.0 |

|Sodium Lauryl Sulphate _ _ 1.0 I

|Emptying Time (mins) 2-3 2-4 6-10 |

IVisual

* Sodium docusate

Further formulations are given in Table 3. These formulations were loaded into a capsule of the type shown in Figure 1, and the delivery times are given in the Table. TABLE 3 - Cutina Based Formulations in controlled release capsule.

% w/w

1A Al A2 C C2 I

|Sodium Bicarbonate 14.2 16.8 14.8 25.8 22.8 |

|Cutina HR 14.2 11.6 10.2 2.6 2.2 |

| Citric Acid 21.6 21.6 25.0 21.6 25.0 |

|Sorbitol 49.5 49.5 45.0 49.5 45.0 |

|Alcopol* 0.5 0.5 - 0.5 | iTween 80 — — 5.0 — 5.0 |

I Pulse Times (hours) -. _ 2.5-4.0 >4.5 4.4 |

* Sodium docusate

EXAMPLE 3 (Adipic Acid Effervescent Formulations)

Adipic acid-containing formulations are given in Table 4 below. These were filled into open-ended polyethylene capsule bodies and the emptying times measured as in Example 1.

TABLE 4

1 mg/Dose 1

ID151/40A D151/40B D151/35A D151/35B D151/35CI

| Lactose 135 135 115 125 135 |

|Sorbitol 135 135 120 130 140 |

|Sodium

| bicarbonate 10 10 40 20 10 |

|Adipic acid 10 - 20 20 10 |

|Citric acid 10 - - |

|Sodium lauryl

| sulphate 10 10 5 5 5 |

|Emptying 10 5-10 vigorous Fairly Slow |

I mins mins release vigorous release| EXAMPLE 5

A further effervescent formulation was produced as follows:

Quantity (mq)

Sucrose 308.45 92%

Dioctyl Sodium Sulphosuccinate 1.46 0.5

Sodium Bicarbonate 5.00 1.5

Citric Acid 10.00 3.0

Cutina HR 5.00 1.5

Active Agent 5.00 1.5 334.91 100.0

The sucrose was granulated with a solution of dioctyl sodium sulphosuccinate and oven dried at 50°C. The Cutina HR was dissolved in isopropyl alcohol, mixed with sodium bicarbonate, screened and dried at 50°C. The materials were then mixed together.

Claims

1. A delivery device for delivering a substance, which comprises a hollow body (6) containing the substance (10) to be delivered, together with an excipient (12) whose volume expands in contact with an aqueous medium such as to expel the substance from the body.

2. A device according to claim 1 wherein the excipient is a material which generates a gas when the excipient comes into contact with the aqueous medium.

3. A device according to claim 2 wherein the gas generating excipient comprises a first component which is a pharmaceutically acceptable carbonate or bicarbonate together with a second component which is a pharmaceutically acceptable acid.

4. A device according to claim 3 wherein the acid is citric acid or adipic acid.

5. A device according to claim 3 or 4 wherein the excipient is in solid form and at least the first component is coated with a water-vapour impermeable coating.

6. A device according to claim 5 wherein the water-vapour impermeable coating is a wax.

7. A device according to claim 6 wherein the wax melts at or below 37°C.

8. A device according to claim 6 or 7 wherein the coating further comprises a water-soluble emulsifying agent.

9. A device according to claim 6, 7 or 8 wherein the coating further comprises a wetting agent.

10. A device according to any of claims 6 to 9 wherein the coating further comprises a sugar.

11. A device according to any of claims 6 to 10 wherein the coating is present in an amount of 10 to 200% by weight of the first component.

12. A device according to any preceding claim wherein the substance to be delivered is present as a layer on the excipient, so as to be closer to a mouth of the body.

13. A device according to any preceding claim, which further comprises a male member (2) engaged with a neck portion of the (female) body (6) , the device including a water-swellable material which swells so as to disengage the female body upon exposure of the device to the aqueous medium, and thereby allows the aqueous medium to come into contact with the expandible excipient within the female body.

14. A device according to claim 13 wherein the male member (2) is a plug, and the plug is formed of said water swellable material.

15. A device according to claim 14 wherein the plug is formed of a hydrogel.