EP0910347A2 - Dispositif distributeur - Google Patents

Dispositif distributeur

Info

Publication number
EP0910347A2
EP0910347A2 EP97918279A EP97918279A EP0910347A2 EP 0910347 A2 EP0910347 A2 EP 0910347A2 EP 97918279 A EP97918279 A EP 97918279A EP 97918279 A EP97918279 A EP 97918279A EP 0910347 A2 EP0910347 A2 EP 0910347A2
Authority
EP
European Patent Office
Prior art keywords
enclosure
aperture
liquid
active material
osmotically active
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97918279A
Other languages
German (de)
English (en)
Inventor
Neil Bonnette Graham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Strathclyde
Original Assignee
University of Strathclyde
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 University of Strathclyde filed Critical University of Strathclyde
Publication of EP0910347A2 publication Critical patent/EP0910347A2/fr
Withdrawn legal-status Critical Current

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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Definitions

  • the present invention relates to a delivery device for delivering a substance into a liquid at a substantially constant rate.
  • the device is particularly, though not exclusively, applicable to the release of pharmaceutical or veterinary substances, but may also be used in a more general context where controlled release is required.
  • Controlled release devices which comprise a tablet coated with a semi-permeable membrane, which allows the passage of water therethrough, having an aperture punched therethrough.
  • the tablet contains an osmotic agent mixed with a drug.
  • water is driven through the semi-permeable membrane into the tablet due to the difference in osmotic pressure.
  • a balancing flow of aqueous solution of drug which has dissolved in the water passes outwardly through the aperture in the semi- permeable membrane under hydraulic pressure. This is alleged to provide a reasonably constant drug delivery over a period of around 24 hours.
  • the present invention provides a delivery device for delivery under osmotic control when in contact with a liquid, which comprises: an enclosure having an enclosure wall and an aperture through the wall; an osmotically active material being present within the enclosure, the material being soluble in the liquid to form a solution; the aperture being sized such that, when the device is in contact with the liquid, osmotically controlled flow of said solution from the enclosure through the aperture occurs.
  • osmotically controlled flow can be achieved through a simple aperture without the need for any semi-permeable membrane.
  • the delivery device of the present invention allows the achievement of a substantially constant rate of delivery in a particularly simple manner. Generally speaking, the rate of delivery is substantially constant until no more osmotically active material is left undissolved within the enclosure. It is surprising that a single aperture is sufficient to allow both the incoming flow (into the enclosure) of liquid and also the outgoing flow of delivered solution.
  • osmotic control means that delivery is determined by the difference in chemical potential (i.e. the partial molar free energy difference) between the solution inside the enclosure and the liquid outside the enclosure. Depending on various parameters including the orientation of the device and density differentials, delivery may be with or without an additional effect due to gravity.
  • the enclosure may be a self-supporting enclosure, such as a bottle, capsule, bag etc., or may be a coating applied onto a solid osmotically active material.
  • the enclosure wall will not include a semi-permeable membrane.
  • the osmotically active material is present in the enclosure in a liquid or solid form, which then dissolves in the liquid.
  • the presence of undissolved osmotically active material helps maintain a solution of substantially constant concentration (e.g. substantially saturated) within the enclosure.
  • a solid osmotically active material may be provided in a suitable solid form, such as a tablet, granule, suppository, pessary etc. Coated granules may be filled into a capsule, such as a hard gelatin capsule, for ease of handling.
  • a larger solid form may be prepared by compaction, such as in a tablet making machine, by moulding a molten or extruded formulation or by other means known in the art.
  • the coating is preferably formed of a polymeric material including homopolymers and/or copolymers, such as a suitably hydrophobic cellulosic polymer, an acrylate, a polyvinyl ester, a polyamide, a polysulphone, a polycarbonate, a polyalkane (such as polyethylene or polypropylene) , a copolymer of ethylene and vinyl acetate, a silicone, or natural or synthetic rubber (such as a homopolymer or copolymer of isoprene or butadiene, or polyisobutene) , or other coating material known in the art.
  • the coating material should, of course, be substantially insoluble in the liquid into which the delivery device is to be brought into contact, and substantially impervious thereto.
  • a liquid osmotically active agent (e.g. glycerol) will generally be soluble in the liquid in all proportions or in limited proportions. Measures may need to be taken to prevent the liquid osmotically active agent from flowing out of the aperture in the enclosure wall.
  • the device will generally be arranged such that the liquid osmotically active agent is kept away from the aperture; such as by providing the aperture at the top of the device when the osmotically active agent is denser than the solution (or at the bottom when it is less dense than the solution) .
  • the aperture in the enclosure wall is typically a circular aperture of diameter 0.01 to 5mm, preferably 0.1 to 1mm.
  • the aperture may be made in any convenient way, such as by drilling or using a laser.
  • a plurality of apertures are formed in the enclosure wall.
  • at least a portion of the enclosure wall is in the form of a microporous membrane comprising a multiplicity of apertures and having a pore size which is typically in the range 0.2 to 5 microns.
  • Such microporous membranes are to be distinguished from the semi-permeable membranes employed in the prior art which typically have pores of the order of a molecular size, for example in the region 1-20 nanometers.
  • Microporous membranes are well known in the art and are typically formed from polymeric materials, such as celluloses, polyamides, polysulphones, polycarbonates, polypropylene, polyethylene, polystyrene, polyurethane, polytetrafluoroethylene, polyvinylidenefluoride; and alumina.
  • microporous membranes are produced by stretching a crystalline polymer film or on a film which has been embossed with a pattern of raised and depressed areas such that pores are formed in the stretched product. Stretching may be uniaxial or biaxial. Other processes involve phase inversion providing pores during membrane formation, and the production of cylindrical pores by radiation track etching.
  • the osmotically active material is delivered from the device under osmotic control.
  • Such osmotically active materials will be present in solid form or liquid form within the enclosure but will be soluble in the liquid to form a solution.
  • the osmotically active material will be water soluble.
  • the device may be designed to operate within other liquids or solutions, including organic or inorganic liquids, in which case the osmotically active material would be chosen to have a suitable solubility in the chosen liquid.
  • the osmotically active agent may, for example, be a salt of a heavy metal ion, such as silver, gold or copper, which may be used for sterilisation purposes.
  • sterilisation applications include the treatment of water tanks in air conditioning units to prevent multiplication of bacteria, and the purification of drinking water in remote areas, countries and conditions where the quality of the water supply is questionable.
  • Peroxides and bleaches for water sterilisation purposes may also be delivered.
  • swimming pools may be treated.
  • Sustained release of copper ions may be useful in marine anti-fouling applications.
  • Complexing agents and acids such as citric acid, sodium citrate, polyphosphoric acid, and polyacrylic acid may be used for descaling or maintaining clean surfaces in hard water areas.
  • the device may also be arranged to deliver dyes, surfactants, scents or fluorescers.
  • the delivery device may be in the form of a toilet block intended to release a dye and/or a disinfecting agent at a substantially constant rate.
  • the device may be arranged to provide a controlled release of fertiliser, nutrient or trace elements at a controlled rate.
  • the regulated supply of selected nutrients to improve growth is an important need which may be met by the simple device of the present invention.
  • the osmotically active material may or may not be the material which it is desired to deliver.
  • the osmotically active material may also function as a vehicle for delivering a different active material, which may be soluble or insoluble in the liquid.
  • the osmotically active material may be a substantially inert material, such as a salt or a sugar whose function is to deliver the different active material within the outgoing solution.
  • a delivery device may be useful for delivering high molecular weight species such as proteins which are difficult to deliver by simple prior art diffusion devices since the diffusion co-efficient decreases dramatically with increasing molecular weight. This type of device may be used to deliver living or dead organisms, or suspended drug particles or other insoluble materials.
  • the insoluble material is generally distributed uniformly throughout the osmotically active material such that it forms a fine dispersion in the liquid as the osmotically active material dissolves.
  • a pigment dispersion in the osmotically active material will be carried by the hydraulic flow of the solution into the external liquid.
  • a finely divided water insoluble drug can be delivered in a similar manner.
  • the osmotically active material may comprise a mixture of such materials where the materials have different solubilities in the liquid, particular delivery characteristics may be provided. For example, a first more soluble material may be delivered first, followed by a second less soluble material. Pulsed or delayed delivery devices may be provided in this way. It is an important feature of the present invention that the delivery (usually in a substantially linear manner) of osmotically active material occurs under osmotic control, that is to say is controlled by the difference in chemical potential of the osmotically active material between the solution inside the enclosure and the liquid outside. Generally speaking, the liquid outside the enclosure is present in a large excess, such that its chemical potential remains essentially constant and is essentially unchanged by the solution passing through the aperture in the enclosure wall.
  • the rate of delivery may also be effected by gravity, where the density of the solution inside the enclosure is different to that of the liquid outside the enclosure; or by diffusion.
  • gravity will depend on the orientation of the delivery device and in many orientations it will be a secondary effect.
  • the size of the aperture will be chosen by simple experimentation in order to provide the desired delivery rate over the chosen period of time. Thus, delivery times may be chosen to be substantially constant over a period of hours, days, weeks or even months.
  • the size of the aperture may also depend upon the solubility of the osmotically active material in the liquid.
  • the size of the aperture and the particle size of a solid osmotically active material will be chosen such that the solid osmotically active material is retained within the enclosure and cannot accidentally pass through the aperture prior to dissolution.
  • Figure 1 shows release profiles from coated tablets having different sized apertures according to Example 1;
  • Figure 2 shows release profile for sodium chloride passing through a microporous membrane;
  • Figure 3 shows a glucose release profile
  • Figure 4 shows a surfactant (sodium lauryl ether sulphate) release profile.
  • a tablet of each type was stirred in a litre of water at 37°C and absorbance readings taken half-hourly for 24 hours. To ensure that the tablets turned over regularly to avoid gravity effects, a stirring speed of 240 rpm was required. In this time the bath concentration of etamiphylline camsylate reached only about 1 microgram/ml, a release of well below 10%.
  • the holes in another pair of Cariflex coated tablets were enlarged with a 1.5 mm drill but the resulting holes were very irregular, and that in the plain white (non- coated) tablet was at least four times the cross sectional area of that in the red (sugar coated) tablet.
  • the stirring speed was reduced to the 60 rpm after about 50 hours without any apparent effect on the release rate.
  • the stirrer for the original white tablet failed at about 100 hours and a subsequent lower release rate can be observed.
  • the rate of drug release from the tablets is linear and dependent on the size of the hole in the impervious coating but is little affected by the red sugar coating.
  • Vials of 5ml capacity were filled with a known weight of solid osmotically active material and then topped up with a saturated aqueous solution thereof.
  • the vials were then sealed with Duropore (trademark) 0.45 microporous membrane.
  • the membrane has a nominal stated pore size of 0.45 microns.
  • Duropore is a hydrophilic vinylidene difluoride microporous membrane supplied by Millipore.
  • Each vial was initially weighed and then placed in water, either in an upright position with the microporous membrane uppermost, in an inverted position, or in a horizontal position. Delivery of osmotically active material was monitored by removing the vials from the water daily, followed by drying and weighing. In some cases the vial was weighed more frequently. In each case the time was noted at which all the remaining solid had dissolved. Enough water was available around the vial so that the concentration of osmotically active material therein never rose higher than 5% by weight.
  • Figure 2 shows the results using sodium chloride as the osmotically active material.
  • the upper three traces show release profiles for sodium chloride with the vial upright in water, the third trace including the presence of a dye mixed with the sodium chloride.
  • the lower three traces show the release profiles for inverted vials.
  • Figure 3 shows release rates for glucose as the osmotically active material both for upright and inverted vials in water.
  • Figure 4 shows the release profile for sodium lauryl ether sulphate surfactant from vials in the upright, horizontal and inverted positions.
  • the rate of release of osmotically active material is substantially constant in all cases up until the last remaining solid material has dissolved.
  • the orientation of the vial has an effect on the actual release rate, due to a contribution from gravity, owing to the density of the solution within the enclosure being higher than that of the surrounding liquid

Landscapes

  • 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)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

L'invention porte sur un distributeur à régulation osmotique lorsqu'il entre en contact avec un liquide, comportant un réceptacle présentant une paroi et au moins un trou dans la paroi. Le réceptacle est rempli d'une substance à activité osmotique et l'ouverture est dimensionnée pour que lorsque le dispositif est en contact avec un liquide, s'établisse un flux à régulation osmotique de solution provenant du réceptacle et traversant l'ouverture.
EP97918279A 1996-05-01 1997-04-30 Dispositif distributeur Withdrawn EP0910347A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9609094 1996-05-01
GBGB9609094.9A GB9609094D0 (en) 1996-05-01 1996-05-01 Delivery device
PCT/GB1997/001192 WO1997040822A2 (fr) 1996-05-01 1997-04-30 Dispositif distributeur

Publications (1)

Publication Number Publication Date
EP0910347A2 true EP0910347A2 (fr) 1999-04-28

Family

ID=10793003

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97918279A Withdrawn EP0910347A2 (fr) 1996-05-01 1997-04-30 Dispositif distributeur

Country Status (3)

Country Link
EP (1) EP0910347A2 (fr)
GB (1) GB9609094D0 (fr)
WO (1) WO1997040822A2 (fr)

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4783337A (en) * 1983-05-11 1988-11-08 Alza Corporation Osmotic system comprising plurality of members for dispensing drug
AU608891B2 (en) * 1987-09-24 1991-04-18 Merck & Co., Inc. Solubility modulated drug delivery device
US4853229A (en) * 1987-10-26 1989-08-01 Alza Corporation Method for adminstering tiny pills
US4931285A (en) * 1988-04-28 1990-06-05 Alza Corporation Aqueous based pharmaceutical coating composition for dosage forms
US5122128A (en) * 1990-03-15 1992-06-16 Alza Corporation Orifice insert for a ruminal bolus
IE920773A1 (en) * 1991-03-12 1992-09-23 Alza Corp Space and stability-efficient delivery device
US5330762A (en) * 1992-02-27 1994-07-19 Alza Corporation Tandospiaine antidepressive therapy
EP0670717B1 (fr) * 1992-11-30 1998-11-25 Pfizer Inc. Dispositif de distribution a membrane de retenue de liquide
US6440457B1 (en) * 1993-05-27 2002-08-27 Alza Corporation Method of administering antidepressant dosage form
US5458887A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
ZA953078B (en) * 1994-04-28 1996-01-05 Alza Corp Effective therapy for epilepsies
US5654005A (en) * 1995-06-07 1997-08-05 Andrx Pharmaceuticals, Inc. Controlled release formulation having a preformed passageway

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9740822A3 *

Also Published As

Publication number Publication date
WO1997040822A2 (fr) 1997-11-06
WO1997040822A3 (fr) 1998-02-19
GB9609094D0 (en) 1996-07-03

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