WO1999011246A1 - Perfectionnements relatifs a des capsules - Google Patents

Perfectionnements relatifs a des capsules Download PDF

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Publication number
WO1999011246A1
WO1999011246A1 PCT/GB1998/002635 GB9802635W WO9911246A1 WO 1999011246 A1 WO1999011246 A1 WO 1999011246A1 GB 9802635 W GB9802635 W GB 9802635W WO 9911246 A1 WO9911246 A1 WO 9911246A1
Authority
WO
WIPO (PCT)
Prior art keywords
capsule
female body
charge
capsule according
male member
Prior art date
Application number
PCT/GB1998/002635
Other languages
English (en)
Inventor
Stephen Donald Mcfarlane
Gerard Atkins
Mark Hegarty
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 BR9811753-0A priority Critical patent/BR9811753A/pt
Priority to CA002302788A priority patent/CA2302788A1/fr
Priority to JP2000508349A priority patent/JP2001514211A/ja
Priority to NZ503164A priority patent/NZ503164A/en
Priority to EP98940458A priority patent/EP1009389A1/fr
Priority to AU88781/98A priority patent/AU734740B2/en
Publication of WO1999011246A1 publication Critical patent/WO1999011246A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • 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

  • This invention relates to an improved capsule and in particular to an improved controlled release capsule for use, for example, in in-vitro tests.
  • the invention further relates to an improved test kit including such a capsule and to an improved test method employing such a capsule.
  • WO 90/09168 discloses a device of this type which comprises a water swellable male hydrogel plug engaged within a female body. A pharmaceutically active material is contained within the device. When the capsule 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 release the pharmaceutical material is predictable and reproducible, so that the device may be used to release pharmaceutically active materials within the body of a patient after a predetermined time interval (e.g. 0.5 to 12 hours).
  • a predetermined time interval e.g. 0.5 to 12 hours.
  • 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 the patient's needs, for example, during the night or when the patient 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.
  • a further improved controlled release capsule is known from WO 94/09745 (R.P. Scherer Corporation) . This type of capsule is known as the "PULSINCAP" (Trade Mark) .
  • controlled release capsules As well as a requirement for controlled release capsules for the administration of pharmaceuticals to human or animal patients, there has also been found to be a need for controlled release capsules in in-vitro test procedures. It has, however, been found that known controlled release capsules suffer from a number of disadvantages, particularly when used in in-vitro tests. For example, it has been found with known capsules that, in use, when the hydrogel plug disengages from the female body the active material contained within the female body may not be completely released therefrom.
  • a controlled release capsule comprising a female body having a charge receiving portion for holding a charge of an agent to be released, a male member engaged within a neck portion of the female body, and buoyant means, wherein, in use, when the capsule is placed in a liquid and at least when the male member is released from the female body the buoyant means cause the female body to orientate such that the charge receiving portion is above the neck portion thereby facilitating release of the charge from the female body.
  • the female body comprises a substantially tubular body having a first end providing the neck portion and a second end providing the buoyancy means.
  • the ratio of length to width of the female body is usually
  • the charge receiving portion is provided between the first and second ends.
  • the charge may be provided in any convenient form, and preferably in the form of a slug. However, it should be appreciated that the charge may alternatively be provided in any suitable form, for example, in the form of tablets, granules, pellet or other dosage units.
  • the buoyancy means formed at the second end of the female body may comprise a cavity formed within the female body.
  • the buoyancy means could be any other way of entrapping air or other gas, such as a sealed enclosure or enclosures, or a foam material.
  • the sealed enclosure could be a hollow sphere of suitable volume (e.g. a hollow soft gelatin capsule) .
  • a plurality of small hollow spheres could also be used.
  • the volume of entrapped gas should be sufficient to invert the capsule, and will be related to the weight of the female body and the weight of the charge.
  • the overall density of the capsule will be greater than the density of the liquid (e.g. 1 g/ml for water) so that the capsule does not float prior to ejection of the male member. It is advantageous if the density of the female body containing the charge is less than the liquid so that the body tends to rise upwards after ejection of the male member, facilitating release of the charge therefrom. Generally, the female body itself will have a density less than that of the liquid, so that the empty body floats upwards, and so assists release of the charge and its distribution through the liquid.
  • the centre of buoyancy of the capsule is spaced away from the (usually heavier) male member so as to provide a maximum turning moment to orient the capsule with the male member (and the first open end of the female body) downwards.
  • the charge receiving portion may communicate with the cavity.
  • the cavity may be of a lesser internal bore than the charge receiving portion at least at an area where the cavity and portion meet, the cavity and portion preferably being joined by a step portion.
  • other ways of spacing a solid charge from the closed second end of the female body so as to maintain a cavity are possible, such as a rod, a series of circumferentially spaced detents, a grid or other way of creating a restriction in cross- section.
  • the slug may be so dimensioned such that it may be inserted into the charge receiving portion but not into the cavity. That is to say an outer dimension of the slug may advantageously be greater than the internal bore of the cavity, such that, upon insertion of the slug a portion of the slug may be caused to abut the step portion.
  • the charge occupies more than 20% of the internal volume of the female body (including any buoyancy cavity) .
  • the female body may be of substantially cylindrical shape, and the second end may further be of substantially hemi-spherical form.
  • the charge receiving portion may be substantially cylindrical .
  • the slug may be substantially cylindrical.
  • the neck portion may provide a tapered portion which tapers outwardly towards the first end.
  • the neck portion may be substantially circular in cross-section.
  • 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 particularly polyethylene, (e.g. low density polyethylene), polypropylene (e.g. grade BK130, T50, or R50) , poly (methylmethacrylate) , polyvinyl chloride, polystyrene, polyurethanes, polytetrafluoroethylene, a nylon, a polyformaldehyde, a polyester, cellulose acetate, a nitro cellulose and gelatin. Generally, the body will be liquid-impermeable and insoluble in the liquid.
  • polyethylene e.g. low density polyethylene
  • polypropylene e.g. grade BK130, T50, or R50
  • poly (methylmethacrylate) polyvinyl chloride
  • polystyrene polyurethanes
  • polytetrafluoroethylene a nylon,
  • one construction may use an ' impermeable coating to cover the exterior of a body which has been formed from a water soluble material.
  • the coating may conveniently be formed by dipping the body in a solution of a material which forms a layer which is impermeable to water.
  • the body might be spray-coated.
  • a preferred class of capsule bodies are conventional hard gelatin or starch capsule bodies coated with a solution of polyvinyl chloride or a polyvinyl acetate copolymer or an ethyl cellulose solution.
  • the male member may comprise a plug, usually of cylindrical configuration.
  • the plug may be of a water swellable material, which is preferably a hydrogel. As it absorbs water, the hydrogel plug swells and becomes disengaged from the female body.
  • the hydrogel is preferably a water swellable material as disclosed in WO90/09168. In its unswollen state, the male member usually occupies 10-30% of the volume of the female body (including any buoyancy cavity) .
  • the neck portion is substantially cylindrical, so as to form a tight fit with the cylindrical male plug.
  • the female body comprises a flared mouth portion adjacent the neck portion, the mouth portion having an entrance which is wider than the neck portion and wider than the male member so as to facilitate insertion of the male member into the neck portion.
  • the flared mouth portion may provide a ramped lead-in, so that the male member may be inserted readily into the neck of the female body.
  • the mouth portion may be flared at an angle of 10° to 60°, preferably 15° - 45°, and most preferably approximately 19° to the line of the capsule.
  • the capsule may be made by known capsule manufacturing techniques, such as injection moulding of thermoplastic materials.
  • the female body may be prepared by conventional capsule forming techniques, which involve dipping a mould pin in a solution of the material from which the capsule is to be formed. Spraying could be used instead of dipping. The material is then dried and stripped from the pin. The capsule body may then be trimmed as necessary.
  • a controlled release capsule which comprises a male member engaged within a neck portion of a female body, the male member being a plug formed of a water swellable material; the female body being adapted to receive a charge of an agent to be released, and to provide a free volume at an end of the body remote from the neck portion, such that when the capsule is placed in a liquid the free volume exerts a buoyancy effect which raises the free volume end of the body above the neck portion of the body and facilitates release of the agent from the body.
  • an in-vitro test kit including a controlled release capsule, the capsule comprising a female body having a charge receiving portion holding a charge of an agent to be released, a male body engaged within a neck portion of the female body, and buoyancy means, wherein, in use, when the capsule is placed in a liquid and at least when the male body is released from the female body the buoyant means cause the female body to orientate such that the charge receiving portion is above the neck portion thereby facilitating release of the charge from the female body.
  • an in-vitro test method comprising the steps of: providing a liquid container containing a select liquid; providing at least one controlled release capsule, the capsule (s) comprising a female body having a charge receiving portion holding a charge of an agent to be released, a male body engaged within a neck portion of the female body, and buoyancy means, wherein, in use, when the capsule is placed in a liquid and at least when the male body is released from the female body the buoyancy means cause the female body to orientate such that the charge receiving portion is above the neck portion thereby facilitating release of the charge from the female body, placing the capsule (s) in the liquid so as to allow the male body to release from the female body, and the female body to orientate such that the charge receiving portion is above the neck portion so as to facilitate release of the agent from the female body into the liquid.
  • the method may be particularly adapted for the cultivation and detection of micro organisms, such as salmonellae.
  • Figure 1 is a sectional side view of a controlled release capsule according to an embodiment of the present invention.
  • Figure 2 is a sectional side view to a reduced scale of a female body of the capsule of Fig. 1 ;
  • Figure 3 is an end view of the female body of Fig. 2;
  • Figures 4 (a) -(e) are a series of schematic diagrams illustrating the capsule of Figure 1, in use. DETAILED DESCRIPTION OF AN EMBODIMENT
  • the capsule 5 comprises a female body 10 having a charge receiving portion 15 holding a charge 20 of an agent to be released, a male member 25 engaged within a neck portion 30 of the female body 10, and buoyancy means hereinafter described.
  • the buoyancy means cause the female body 10 to orientate such that the charge receiving portion 15 is above the neck portion 30 thereby facilitating release of the charge 20 from the female body 10.
  • the female body 10 comprises a substantially tubular body having a first end 35 providing the neck portion 30 and a second end 40 providing the buoyancy means.
  • the charge receiving portion 15 is provided between the first and second ends 35,40.
  • the charge 20 is in the form of a slug.
  • the charge may alternatively be provided in any suitable form, for example, in the form of tablets, granules, pellet or other dosage units.
  • the buoyancy means formed at the second end 40 of the female body 10 comprise a domed air filled cavity 45 formed with the female body 10.
  • the charge receiving portion 15 communicates with the cavity 45.
  • the cavity 45 is of a lesser internal bore than the charge receiving portion 15 at an area where the cavity 45 and portion 15 meet, the cavity 45 and portion 15 being joined by a step portion 50.
  • the charge slug 20 is dimensioned such that it can be inserted into the charge receiving portion 15 but not into the cavity 45. That is to say an outer dimension of the charge slug 20 is greater than the internal bore of the cavity 45, such that upon insertion of the charge slug 20 into the portion 15 the charge slug 20 may be caused to abut the step portion 50.
  • the female body 10 is of substantially cylindrical shape, the second end further being substantially of hemi-spherical form. Further the charge receiving portion 15 is substantially cylindrical, as is the charge slug 20.
  • the neck portion 30 is provided with an outmost cylindrical portion 55 and a tapered portion 60 of frusto-conical form which tapers outwardly towards the first end 35.
  • the tapered portion 60 is flared at an angle of approximately 19° to either side of a centre line of the capsule 5.
  • Walls of the female body 10 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 particularly polyethylene (e.g. low density polyethylene) , polypropylene (e.g. BK 130, T50, R50) , or alternatively poly (methylmethacrylate) , polyvinyl chloride, polystyrene, polyurethanes, polytetrafluoroethylene, nylons, polyformaldehydes, polyesters, cellulose acetate and nitro cellulose.
  • polyethylene e.g. low density polyethylene
  • polypropylene e.g. BK 130, T50, R50
  • poly (methylmethacrylate) polyvinyl chloride
  • polystyrene polyurethanes
  • polytetrafluoroethylene polytetrafluoroethylene
  • nylons polyformaldehydes
  • polyesters cellulose acetate and nitro
  • the male member 25 is in the form of a plug of part cylindrical configuration.
  • the male member 25 formed of a water swellable material, which is preferably a hydrogel. As it absorbs water, the hydrogel plug swells and becomes disengaged from the female body 10.
  • the hydrogel is preferably a water swellable material as disclosed in WO90/09168.
  • the neck portion 30 is substantially cylindrical, so as to form a tight fit with the cylindrical part of male member 25.
  • the outermost cylindrical portion 55 is 0.25mm long and 7.00mm in internal diameter to allow the male body 25 to sit square in the neck portion 30 of the capsule 5.
  • the tapered portion 60 is 0.55mm long, over which the internal diameter is reduced from 7.00mm to 6.62mm. When fitted flush the majority of the male member 25 sits in the neck portion 30 of the capsule 5 with an internal diameter of 6.62mm, 5mm long. Using this capsule 5 it is possible to use a range of male member 25 plug lengths between 3.00mm and 5.8mm.
  • the capsule body is generally produced by injection moulding in a mould cavity provided with a retractable mould pin. Ridge 47 engages a corresponding groove on the mould pin and retains the body as it is withdrawn from the mould cavity.
  • Polypropylene is a preferred material and the finished body has a flexural modulus of elasticity (ASTM D790) of 1700 MPa.
  • the capsule body may be prepared by conventional capsule forming techniques, which involve dipping a mould pin in a solution of the material from which the capsule 5 is to be formed. Spraying could be used instead of dipping. The material is then dried and stripped from the pin. The female body 10 may then be trimmed as necessary.
  • the capsule 5 may be employed as part of a test kit such as an in-vitro test kit, for example, for the cultivation and detection of salmonellae.
  • the capsules 5 can be used to deliver a selected bacteride after a selected time delay/ incubation period of, for example, 4 to 6 hours.
  • a person wishing to undertake an in-vitro test will follow the steps of: providing a suitable liquid container containing a selected aqueous liquid as is known in the art; provide at least one capsule 5; placing the/each capsule 5 in the liquid such that hydration of the male body(ies) 25 after a predetermined time(s) causes the/each capsule 5 to orientate with the neck portion (s) 30 below the charge receiving portion (s) 15 and thence the male body(ies) 25 to eject from the female body(ies) 10 causing the charge slug(s) 20 to exit the female body(ies) 10 into the liquid.
  • 225ml of purified water or other aqueous medium is placed into each of a series of dissolution pots at 20°C( ⁇ 2°C) .
  • the test is started by placing six capsules 5 into each pot, switching on a heater, with the thermostat set at 35°C and starting stirring paddles at 50rpm. After 2 hours the thermostat temperature is increased to 42°C.
  • the majority, if not all, of the capsules 5 should be orientated with the male body 25 end down. Prior to ejection, as the male member 25 begins to extract itself from the female body 10, the capsule 5 will begin to float with the male body 25 end down. When the male member 25 finally separates from the capsule 5 the charge slug 20 will fall to the bottom of the dissolution pot.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Medicinal Preparation (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pens And Brushes (AREA)

Abstract

Selon cette invention, une capsule pour libération contrôlée comporte un corps femelle (10) doté d'une partie (15) réceptrice de charge destinée à retenir une charge (20) d'un agent devant être libéré. Un organe mâle obturateur (25), qui gonfle au contact de l'eau, est inséré dans une partie col (30) du corps femelle. Un organe de flottaison (45) est destiné à maintenir l'extrémité fermée du corps femelle en haut, de sorte que lorsque l'organe mâle est libéré du corps femelle, l'organe de flottaison provoque l'inclinaison du corps femelle en vue de faciliter la libération à partir de ce dernier de la charge soumise à la gravité. Cet agencement favorise le vidage rapide de la charge contenue dans la capsule après le gonflement et la séparation de l'organe mâle obturateur.
PCT/GB1998/002635 1997-09-04 1998-09-02 Perfectionnements relatifs a des capsules WO1999011246A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR9811753-0A BR9811753A (pt) 1997-09-04 1998-09-02 Aperfeiçoamentos em ou referentes a cápsulas
CA002302788A CA2302788A1 (fr) 1997-09-04 1998-09-02 Perfectionnements relatifs a des capsules
JP2000508349A JP2001514211A (ja) 1997-09-04 1998-09-02 放出を制御されるカプセル、該カプセルを有する微生物の培養および検出用テストキット
NZ503164A NZ503164A (en) 1997-09-04 1998-09-02 Controlled release capsule for use in in-vitro testing
EP98940458A EP1009389A1 (fr) 1997-09-04 1998-09-02 Perfectionnements relatifs a des capsules
AU88781/98A AU734740B2 (en) 1997-09-04 1998-09-02 Improvements in or relating to capsules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9718664.7 1997-09-04
GBGB9718664.7A GB9718664D0 (en) 1997-09-04 1997-09-04 Improvements in or relating to capsules

Publications (1)

Publication Number Publication Date
WO1999011246A1 true WO1999011246A1 (fr) 1999-03-11

Family

ID=10818455

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/002635 WO1999011246A1 (fr) 1997-09-04 1998-09-02 Perfectionnements relatifs a des capsules

Country Status (8)

Country Link
EP (1) EP1009389A1 (fr)
JP (1) JP2001514211A (fr)
AU (1) AU734740B2 (fr)
BR (1) BR9811753A (fr)
CA (1) CA2302788A1 (fr)
GB (1) GB9718664D0 (fr)
NZ (1) NZ503164A (fr)
WO (1) WO1999011246A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10076500B2 (en) 2010-07-05 2018-09-18 Jagotec Ag Floating gastric retentive dosage form

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4055178A (en) * 1976-03-10 1977-10-25 Harrigan Roy Major Drug delivery device for preventing contact of undissolved drug with the stomach lining
EP0326816A1 (fr) * 1988-02-05 1989-08-09 LTS Lohmann Therapie-Systeme GmbH & Co. KG Système thérapeutique oral capable de flotter
WO1990009168A1 (fr) 1989-02-16 1990-08-23 National Research Development Corporation Dispositif de distribution
US5198229A (en) * 1991-06-05 1993-03-30 Alza Corporation Self-retaining gastrointestinal delivery device
WO1994009745A1 (fr) 1992-11-05 1994-05-11 R.P. Scherer Corporation Structure de capsule

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4055178A (en) * 1976-03-10 1977-10-25 Harrigan Roy Major Drug delivery device for preventing contact of undissolved drug with the stomach lining
EP0326816A1 (fr) * 1988-02-05 1989-08-09 LTS Lohmann Therapie-Systeme GmbH & Co. KG Système thérapeutique oral capable de flotter
WO1990009168A1 (fr) 1989-02-16 1990-08-23 National Research Development Corporation Dispositif de distribution
US5198229A (en) * 1991-06-05 1993-03-30 Alza Corporation Self-retaining gastrointestinal delivery device
WO1994009745A1 (fr) 1992-11-05 1994-05-11 R.P. Scherer Corporation Structure de capsule

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10076500B2 (en) 2010-07-05 2018-09-18 Jagotec Ag Floating gastric retentive dosage form

Also Published As

Publication number Publication date
AU8878198A (en) 1999-03-22
GB9718664D0 (en) 1997-11-05
CA2302788A1 (fr) 1999-03-11
AU734740B2 (en) 2001-06-21
EP1009389A1 (fr) 2000-06-21
JP2001514211A (ja) 2001-09-11
BR9811753A (pt) 2001-11-27
NZ503164A (en) 2001-07-27

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