WO1995013056A1 - Dispositif de liberation - Google Patents

Dispositif de liberation Download PDF

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Publication number
WO1995013056A1
WO1995013056A1 PCT/GB1994/002468 GB9402468W WO9513056A1 WO 1995013056 A1 WO1995013056 A1 WO 1995013056A1 GB 9402468 W GB9402468 W GB 9402468W WO 9513056 A1 WO9513056 A1 WO 9513056A1
Authority
WO
WIPO (PCT)
Prior art keywords
plug
active material
water
capsule
unit dosage
Prior art date
Application number
PCT/GB1994/002468
Other languages
English (en)
Inventor
Abdul Rashid
Howard Norman Ernest Stevens
Massoud Bakhshaee
Julie Stephanie Binns
Christopher Jon Miller
Original Assignee
R.P. Scherer Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by R.P. Scherer Corporation filed Critical R.P. Scherer Corporation
Priority to AU81130/94A priority Critical patent/AU8113094A/en
Publication of WO1995013056A1 publication Critical patent/WO1995013056A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the present invention relates to a controlled release capsule for delivering active materials, which comprises a male member engaged within a female body; a water-swellable material being provided which swells so as to disengage the female body upon exposure to an aqueous medium.
  • the active material may be delivered to a patient at a chosen time (e.g. 0.5 to 12 hours) following administration.
  • This may, for example, be useful in the treatment of medical conditions where it is desirable to administer a pharmaceutically active material to the 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, for example 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 so as to open the device.
  • the expansion means may be a swellable polymer or an osmotic formulation which swells as it absorbs fluid.
  • 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 pharmaceutically active material contained within the body of the device is in the form of powder or granules.
  • the pharmaceutically active material is released from the body promptly once the hydrogel plug has been ejected.
  • a pulse of drug at a desired time is required.
  • a particular application of the controlled release device is release of pharmaceutically active material into the colon.
  • the waste material contained therein has a particularly high solids content and a particularly low water content. This exacerbates the problem of effectively releasing the contents of the controlled release device into the surrounding fluid so that it becomes available for absorbtion into the patient's system.
  • the relatively low water content means that a minimal amount of water is available for flushing or dissolving the pharmaceutically active material from within the controlled release device.
  • the high solids content means that there is a relatively low degree of agitation within the colon, so that there is a reduced likelihood of the contents of the controlled release device being expelled by movement of the device within the gastro-intestinal tract.
  • the present invention provides a controlled release capsule for delivering an active material, which comprises a male member engaged within a neck portion of a female body; the capsule including a water-swellable material which swells so as to disengage the female body upon exposure of the capsule to an aqueous medium; and a unit dosage of said active material supported on either the male member or the female body, and the other thereof protecting the unit dosage from the aqueous medium prior to disengagement.
  • the capsule comprises a male plug engaged within a female body; the male plug being formed from a water-swellable material which swells so as to disengage the female body upon exposure to an aqueous medium and a unit dosage of active material supported on the male plug, the female body surrounding the unit dosage and protecting it from the aqueous medium prior to disengagement.
  • the principle of the present invention is that the active material is associated with the male plug and therefore becomes detached from the body and subject to the surrounding aqueous environment on disengagement of the plug.
  • delivery of the active material from the capsule occurs at substantially the same time as the plug is ejected, thereby substantially avoiding any problems associated with complete emptying of the active material from the capsule.
  • the active material is provided within a recess in the inside end of the plug (i.e. that which faces the body).
  • the recess is centrally located in the rear face of the plug.
  • the recess may be formed by drilling into the rear face of the plug, for example using a laser or mechanical drill, or by moulding.
  • the recess is up to 4mm in diameter, usually 2 to 3 mm in diameter; and up to 2mm, preferably up to l.7mm deep. The dimensions will vary depending on the size of the plug and the amount of active material to be administered.
  • the recess size can be up to 50% of the diameter of the plug and up to 50% of the length, though both should not approach the upper end of these ranges at the same time.
  • More than one recess may be provided in the rear of the plug.
  • the recess might also be in the form of one or more channels formed in the end of the plug.
  • the channels might be in the form of a series of parallel channels, concentric circles, a grid pattern or other such arrangement.
  • the recess may be loose filled with powder, pellets or granules or may be filled with a liquid, paste or melted solid material.
  • the recess is preferably sealed with a water-soluble material, such as gelatin or polyvinylpyrrolidone paste.
  • the pharmaceutically active material is in a solid form
  • the solid material e.g. in the form of a cylinder
  • the solid material may project out beyond the surface of the plug.
  • the recess tends to become distorted, such that the mouth of the recess is enlarged.
  • a cylindrical recess may become slightly frustro-conical. This may be advantageous in that it facilitates ejection of the pharmaceutically active material from the plug and expedites exposure to the surrounding aqueous medium. If desired, the effect may be accentuated by initially forming the recess in a frustro-conical or other outwardly tapering configuration.
  • the pharmaceutically active material may be any of those disclosed in W090/09168.
  • the capsule body may be bulked out with an inert material, such as lactose, or may be provided with an additional or different active material depending on the desired dosage regime.
  • the body might also contain a material which expands in the presence of water (such as hydrogel powder or a swellable disintegrant material) and pushes the plug away from the body after disengagement, so assisting dissolution of the active material.
  • the pharmaceutically active material is adhered to the rear face of the hydrogel plug.
  • the active material is in a solid or other suitable dosage form, such as a tablet, granules and hard or soft capsules.
  • This form of the invention is particularly advantageous where larger amounts of pharmaceutical formulation have to be administered.
  • the maximum size of solid material on the back of the plug is, of course, limited by the available volume of the capsule body. However, close tolerances between the solid material and the body should be avoided in order to facilitate complete disengagement of the plug and pharmaceutically active material from within the capsule body.
  • the volume of solid material is less than 50% of the available (i.e. that remaining after the plug has been inserted) body volume.
  • the solid material on the back of the plug becomes immediately exposed on its sides and free end to the aqueous surroundings, a rapid delivery time and complete emptying of the active material from the body is possible.
  • other release profiles may be provided and these may depend on the formulation of the dosage, such as freeze dried tablet, gastroresistant dose, sustained release tablet, pure active etc.
  • the solid material, such as a tablet is arranged to dissolve or disintegrate on exposure to aqueous medium.
  • the pharmaceutically active material may be any of those disclosed in W090/09168 without being limited to these.
  • the solid active material may be adhered to the plug using an adhesive which is water soluble or water-insoluble.
  • the adhesive should be arranged so that the active material is retained on the back of the plug, even when the plug becomes hydrated, until after disengagement of the plug.
  • Suitable adhesives include polyvinylpyrrolidone, and conventional film formers; pH sensitive polymers may also be used, as well as gelatin - glycerol mixtures. Enteric coatings may be applied.
  • the invention also relates to a corresponding process of filling the capsule which comprises storing the caps and bodies separately, introducing the plug and dose of active material into the neck of the body, and fitting a cap over the open end of the body.
  • the proposed arrangement ensures that the pharmaceutically active material becomes ejected into the gastrointestinal fluid together with the hydrogel plug as the plug becomes disengaged. If required, a sharp predictable pulse (or other desired release profile) of pharmaceutically active material is thus achieved.
  • 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 controlled release device which serves to disengage the female body after a pre-determined 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 controlled release device may be an osmagent or an osmopolymer. Such an arrangement is disclosed in patent specification W092/13521.
  • a portion of the wall of the device adjacent thereto is preferably semi-permeable, 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.
  • the unit dosage of active material may be attached to a movable partition of the type provided in W092/13521 which moves within the female body as the water-swellable material expands to disengage the male member and the female body.
  • Figure 1 is a sectional elevation of a first embodiment having a tablet on the back of the plug; and Figure 1A shows an alternative capsule construction as employed in Examples 8 and 9.
  • Figure 2 shows a second embodiment where the pharmaceutically active material is contained within a recess in the back of the plug
  • Figure 3 shows a typical drug release profile from a hole in the plug arrangement (Example 2) ;
  • Figures 4 and 5 show release profiles for embodiments having a tablet on the back of the plug (for Examples 6 and 8 respectively) .
  • the capsule comprises a male plug 2 formed of a hydrogel material inserted in the neck 4 of the female body 6.
  • the capsule is closed with a water-soluble cap 8.
  • the male plug 2 is formed of a hydrogel material, (such as disclosed in W090/09168) and is usually inserted so that the upper end of the plug is level with or below the end of the neck of the capsule body.
  • the water-soluble cap is preferably formed of gelatin.
  • the capsule body may be formed of a water-insoluble material, which may be a water-insoluble plastics material, or may be gelatin coated with a water-impermeable coating.
  • a tablet 9 (whose size may be extended as shown in dotted lines) is adhered to the rear face 10 of the hydrogel plug by means of a suitable adhesive which may be water-soluble, water-insoluble or pH sensitive.
  • a water-soluble adhesive might be polyvinylpyrrolidone or a gelatin-glycerol mixture.
  • the tablet is located on the rear face of the plug so that it contacts the area of the plug which is least hydrated prior to disengagement of the plug. Also, sufficient clearance between the tablet and the capsule body should be provided to facilitate complete expulsion of the plug and tablet from within the body.
  • Figure 1A shows an alternative capsule construction as employed in Examples 8 and 9 wherein the neck region 4 is of reduced diameter and the upper end of the neck is flared.
  • FIG. 2 shows a further embodiment which is useful where small amounts of pharmaceutical compositions are to be dosed.
  • a recess 12 is provided in the rear inner face of the plug 2.
  • the recess is generally cylindrical and has been formed by drilling.
  • the hydrogel plug is 6.9mm in diameter and 3.0mm long;
  • the recess is centrally located and is typically 3mm in diameter and sufficiently deep.
  • the recess is located in the last area of the hydrogel plug to swell. However, should limited hydration occur, this may be beneficial in widening the mouth of the recess and facilitating expulsion of the pharmaceutically active material.
  • the active material is in the form of a paste or powder which has been filled into the recess.
  • the plug is then inserted into the neck of the capsule in the normal way.
  • the capsule In use, the capsule is administered to a patient and passes into the stomach.
  • the aqueous environment in the stomach quickly dissolves the water-soluble cap.
  • Water is then absorbed into the hydrogel plug, which swells and is expelled from the capsule body after a predetermined time interval (for example 1 to 10 hours) carrying with it the pharmaceutically active material.
  • the pharmaceutically active material then becomes exposed to the surrounding aqueous medium in the gastrointestinal tract and any water-soluble adhesive or retaining film is dissolved, leading to dissolution of the pharmaceutically active material.
  • the capsule is enteric-coated so as to pass through the stomach unaffected, and the coating dissolving in the intestine where the pH is relatively high.
  • enteric coating includes all coatings (whether pH dependent or not) which are able to pass through the stomach and dissolve in the intestine. This includes coating materials, such as fats, which dissolve preferentially under the enzymatic regime prevailing in the intestine.
  • the invention is useful inter alia for delivery of active material in the colon, where low levels of liquid are present.
  • the Amberlite (trademark) ion-exchange resin was ground to a powder in a pestle and mortar before use.
  • the mixture was then formed into a tablet 5mm in diameter and 4mm long using a hand tabletting press.
  • sucrose and ion-exchange resin were included in the mixture as vehicles for attaching radioactive labels.
  • a paste was made up from the polyvinylpyrrolidone and the water, to which the lactose was then added.
  • Each tablet was then adhered to the back of a hydrogel plug using a small amount of the adhesive paste.
  • the plug dimensions are given in Table 3.
  • Each hydrogel plug and tablet was fitted into the neck of a capsule body.
  • the capsule body had a neck of reduced diameter compared to the rest of the body and the upper end of the neck was flared; as shown in Figure 1A.
  • the plug was either flush or recessed below the upper end of the neck of the body and the tablet was on the inside of the plug.
  • Each body was filled with a hydrogel powder which swells in contact with water and assists complete separation of the plug after disengagement from the body.
  • a water-soluble gelatin cap was clipped over the neck of the body.
  • a pair of capsules (of nominal disengagement time 5hrs and 15hrs respectively) was then placed in a series of vessels each containing 11 of water at 37°C stirred by a paddle at 50rpm.
  • a stainless steel spring was fitted around the body of each capsule to weigh it down. Water from the vessel was circulated by a pump from the vessel into a UV cell (and then returned to the vessel) and the UV absorption at 254nm was monitored spectroscopically as a measure of quinine released into the water.
  • Example 8 Eleven healthy volunteers (6 male, 5 female, and aged 20-29) who had fasted were each dosed by mouth with a controlled release capsule of the type shown in Figure 1A and described in Example 8 having a nominal disengagement time of 5 hrs. Each capsule contained a tablet adhered to the underside of the plug. The tablets were formulated as in Example 8 to contain a radiolabelled marker (Indium 111) bound to the Amberlite ion exchange resin to indicate the time and site of release of the tablet; together with quinine to enable absorption to be monitored.
  • a radiolabelled marker Indium 111
  • Amberlite ion exchange resin to indicate the time and site of release of the tablet
  • 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 tubular polytetrafluoroethylene moulds 25cm long under a vacuum of less than 50 millibars. Curing took place at 95°C for 4 hours in a fan equipped oven. The 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.
  • BHA butylated hydroxy anisole
  • 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.
  • hydrogel rod was then cut into plugs, each generally of a nominal length 4mm, for use in the capsule of the invention as previously described.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une gélule à libération régulée destinée à libérer une dose unitaire d'un principe actif dans le corps d'un patient à un moment prédéterminé après avoir été administrée, comprend un tampon mâle d'hydrogel (2) introduit dans le col (4) d'une partie creuse (6). la dose unitaire sous forme solide est fixée sous la forme d'un comprimé (9) dans l'extrémité intérieure du tampon mâle, ou est logée dans un évidement (12) ménagé dans ladite extrémité. Lorsque l'on place le dispositif dans un milieu aqueux (par exemple le tractus gastro-intestinal), le tampon d'hydrogel se gonfle et se dégage de la partie creuse après une période de temps prédéterminée, portant avec lui le dosage unitaire, lequel est ainsi effectivement libéré hors de la partie creuse, le liquide aqueux contribuant ensuite à sa dissolution.
PCT/GB1994/002468 1993-11-11 1994-11-10 Dispositif de liberation WO1995013056A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU81130/94A AU8113094A (en) 1993-11-11 1994-11-10 Dispensing device

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939323261A GB9323261D0 (en) 1993-11-11 1993-11-11 Dispensing device
GB9323261.9 1993-11-11

Publications (1)

Publication Number Publication Date
WO1995013056A1 true WO1995013056A1 (fr) 1995-05-18

Family

ID=10744998

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1994/002468 WO1995013056A1 (fr) 1993-11-11 1994-11-10 Dispositif de liberation

Country Status (3)

Country Link
AU (1) AU8113094A (fr)
GB (1) GB9323261D0 (fr)
WO (1) WO1995013056A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026853A1 (fr) * 1997-11-20 1999-06-03 R.P. Scherer Corporation Dispositif a liberation retardee
US7163693B1 (en) 1999-07-30 2007-01-16 Smithkline Beecham Plc Multi-component pharmaceutical dosage form

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4898733A (en) * 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
EP0384646A1 (fr) * 1989-02-16 1990-08-29 Btg International Limited Dispositif de délivrance d'un principe actif

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4898733A (en) * 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
EP0384646A1 (fr) * 1989-02-16 1990-08-29 Btg International Limited Dispositif de délivrance d'un principe actif

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026853A1 (fr) * 1997-11-20 1999-06-03 R.P. Scherer Corporation Dispositif a liberation retardee
US7163693B1 (en) 1999-07-30 2007-01-16 Smithkline Beecham Plc Multi-component pharmaceutical dosage form
US7691407B2 (en) 1999-07-30 2010-04-06 Smithkline Beecham Plc Multi-component pharmaceutical dosage form

Also Published As

Publication number Publication date
AU8113094A (en) 1995-05-29
GB9323261D0 (en) 1994-01-05

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