EP0776196A1 - Dispositif hydrophile a liberation modulee - Google Patents

Dispositif hydrophile a liberation modulee

Info

Publication number
EP0776196A1
EP0776196A1 EP95928589A EP95928589A EP0776196A1 EP 0776196 A1 EP0776196 A1 EP 0776196A1 EP 95928589 A EP95928589 A EP 95928589A EP 95928589 A EP95928589 A EP 95928589A EP 0776196 A1 EP0776196 A1 EP 0776196A1
Authority
EP
European Patent Office
Prior art keywords
body according
hydrophilic
coating
water
surfactant
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Withdrawn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
EP95928589A
Other languages
German (de)
English (en)
Inventor
Graeme Scott Macleod
Christopher Jon Miller
David Kean Macrae
Howard Norman Ernest Stevens
Mark Hegarty
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.)
Catalent Pharma Solutions Inc
Original Assignee
Catalent Pharma Solutions Inc
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 Catalent Pharma Solutions Inc filed Critical Catalent Pharma Solutions Inc
Publication of EP0776196A1 publication Critical patent/EP0776196A1/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Withdrawn legal-status Critical Current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
    • A61K9/48—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A61J3/071—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of telescopically engaged two-piece capsules
    • 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

Definitions

  • the present invention relates to controlled release devices intended for containing an active material (especially a pharmaceutically active material) which are arranged to release the active material after a predetermined time interval.
  • an active material especially a pharmaceutically active material
  • a controlled release 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, which may be in the form of capsule.
  • the male plug which is typically formed of a hydrogel material swells and eventually disengages itself from the female body; thereby allowing the pharmaceutically active material contained within the capsule to be released. It has been found that the time taken to disengage the hydrogel plug and so open the device 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, which is typically in the range 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 active material in the patient at a time 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 device In order for the pharmaceutically active material to be effectively released from the controlled release device, two things must occur. Firstly, the device must become opened by detachment of the male and female sections so as to enable the entry of liquid. Secondly, liquid must in fact enter the device so as to enable the pharmaceutically active material to be flushed out of the device into the surrounding liquid. Since the objective is to enable the patient to be dosed with the pharmaceutically active material at a chosen time, both these steps must occur.
  • the present invention is particularly concerned with the second step, that is to say with ensuring that an effective release of material occurs, following opening of the controlled release device.
  • 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 water- impermeable body for a controlled release device for containing a material to be released when the body is immersed in an aqueous liquid, the body having an opening through which the material is released from the body, the interior surface of the body at least in a region thereof adjacent the opening comprising a hydrophilic material.
  • the present invention resides in coating or otherwise providing at least a portion of the interior surface of the body adjacent the opening with a hydrophilic material which facilitates ingress of aqueous liquid from the surroundings.
  • the material to be released from the controlled release device is a powdered material or other solid material which is inevitably filled into the body together with a quantity of air. This may be equally true when liquid fillings are provided within the controlled release device.
  • the present inventors have observed that when the body becomes opened by release of the male and female sections of the device, there is a tendency for an air bubble to form within the area of the opening, and this air bubble inhibits ingress of aqueous liquid into the capsule body.
  • the present inventors have successfully addressed this problem by coating the interior surface adjacent the opening in the body, which is the area in which the air bubble or bubbles normally collect, with a hydrophilic material.
  • the hydrophilic material is normally present as a coating, but may if necessary be formed as an intrinsic part of the material from which the body is formed. It is believed that the provision of the hydrophilic material helps release the air bubble from its position obstructing the opening to the body. Release of the air bubble may be facilitated by a change in the surface energy of attraction of the air for the interior surface of the body, or more likely by promoting the wetting of the interior surface of the body by aqueous liquid and thus promoting the flow of aqueous liquid into the body and thereby forcing the air bubble out.
  • the present inventors do not wish to be limited by any particular theory of operation. As will be demonstrated herein, the provision of a hydrophilic surface in this way is particularly effective in removing the air bubble from the opening of the body of the controlled release device.
  • the body is in the form of a capsule body prepared by conventional capsule forming techniques, which generally involve dipping a mould pin in a solution of the material (such as gelatin) from which the capsule is to be formed. Spraying could be used instead of dipping. The gelatin is then dried and stripped from the pin. The capsule body may then be trimmed as necessary.
  • the capsule body might be made by other known manufacturing techniques, such as injection moulding of thermoplastic materials.
  • the water-impermeable wall of the body intended to contain the active material may be formed from a wide variety of materials.
  • the wall of the body is impermeable to water (and generally also insoluble in water) such that aqueous liquid cannot enter the body until the body has opened after the predetermined time interval.
  • water-impermeable we mean that substantially no water passes through the coating during the normal period in which the body is in contact with aqueous liquid up to opening of the controlled release device.
  • the wall of the body may be of homogenous construction or may be laminated.
  • Examples of materials suitable for use in the construction of the body include polyethylene, polypropylene, poly (methyl ethacrylate ) , polyvinylchloride, polystyrene, polyurethanes, polytetrafluoroethylene, nylons, polyformaldehydes, polyesters, cellulose acetate and nitrocellulose.
  • a preferred construction uses a water- impermeable coating to cover the exterior of a body which has been formed from a water-soluble material since this may be conveniently made using conventional technology.
  • the coating may 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 polyvinylchloride, a polyvinyl acetate copolymer or an ethyl cellulose solution and dried to form a water- impermeable coating.
  • the body is a female body which comprises a male member engaged within the opening.
  • the male member may be a plug provided within a neck portion of the body adjacent the opening thereof.
  • the plug is usually of substantially cylindrical configuration and may be formed of a water-swellable material, 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 patent specification W090/09168.
  • the neck portion is substantially cylindrical, so as to form a tight fit with the cylindrical male plug.
  • 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 permeaole to the passage of water into the device but impermeable to release of other substances from within the device.
  • the efficient removal of air bubble(s) from the opening to the body requires that the interior surface of the body in the region adjacent the opening be of a hydrophilic material.
  • the body itself may be formed from a suitable hydrophilic material, but generally speaking the choice of suitable materials is limited, since hydrophilic materials tend to be water soluble and run the risk of allowing water to enter through the wall of the capsule body prior to opening of the device.
  • the body is more usually formed of a material which is water-insoluble or which has been coated with a water- insoluble coating. Such water-insoluble materials by their nature terd not to be hydrophilic. Therefore, in a preferred embodiment of the present invention, the hydrophilic material is provided as a coating.
  • the coating may be provided in any suitable manner, such as by dip coating or spray-coating. Where spray coating is employed, it is found that sufficient of the hydrophilic coating material becomes sprayed through the opening of the body to effectively coat the region of the interior surface of the body immediately adjacent to the opening, where there is a likelihood of air bubble lodgement. It is not generally speaking necessary that the whole of the interior surface of the body be coated with the hydrophilic material.
  • the hydrophilic material may generally be applied by application of a solution or suspension of the hydrophilic material in a suitable aqueous or organic liquid vehicle.
  • the coating should be a smooth coherent coating which is non-tacky, so that the normal flow characteristics of the controlled release devices, (e.g. capsules), are unimpaired and clumping does not occur.
  • the material should generally dry to a solid coating.
  • the hydrophilic material may comprise a suitable surfactant material provided that it fulfils the criteria set out above.
  • film forming materials of a hydrophilic nature may be used and a multitude of such materials are known in the art.
  • the film forming material may be insoluble in water or may have water solubility. Other things being equal, water soluble coatings tend to exhibit relatively good emptying properties.
  • mixtures of film forming materials and surfactants may be employed, and these have been found to be particularly useful in enhancing the hydrophilic properties of the film former.
  • Suitable film forming materials of varying hydrophilicity include celluloses, polyacrylates, poly ethacrylates, polyacrylamides, polyvinyl alcohols, and polyvinylpyrrolidones.
  • Specific film forming materials include hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, acrylic resins such as Eudragits (trade mark) , hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, zein, shellac, cellulose acetate and cellulose triacetate.
  • suitable sugar-based coating materials such as sugar, gelatin, acacia gum and starch.
  • Suitable surfactants for inclusion in the hydrophilic coating include anionic, nonionic and cationic surfactants. Typical examples include sodium lauryl sulphate, sodium docusate, sodium oleate, castor oils, hydrogenated castor oils, fatty acid esters, and fatty acid alcohols (e.g. cetyl and lauryl) .
  • the surfactant may also be a polyoxyethylene or derivative thereof, such as polyoxyethylene sorbitan monolaurate (e.g. Tweens) , polyoxyethylene sorbitan monooleate (e.g.
  • Spans fatty acid ethoxylates such as polyoxyethylene stearate, alcohol ethoxylates such as polyoxyethylene oleylether, polyoxyethylene-polyoxypropylene copolymers, and polyethylene glycols.
  • Span and Tween are trade marks.
  • a particularly preferred embodiment of the present invention employs a conventional hard gelatin capsule body which has been coated with ethyl cellulose to make it water insoluble.
  • the capsule body is spray coated with a further coating of ydroxypropylmethyl cellulose (HPMC) .
  • HPMC ydroxypropylmethyl cellulose
  • gelatin may be used as the hydrophilic coating over the water insoluble capsule body, in order to give the capsule a familiar appearance and feel to a patient.
  • the hydrophilic coating generally comprises from 0.1 to 50% by weight of the body of the controlled release device, particularly 1 to 20% by weight, especially 2 to 10% by weight.
  • the hydrophilic nature of the hydrophilic material may be quantified in terms of the advancing contact angle of the material (which may be measured using the standard Wilhelmy plate technique) , which reflects the surface activity of the material.
  • the advancing contact angle is less than 80°, preferably less than 75°, and advantageously less than 70°. It may lie in the range of 50 to 75°, particularly 60 to 70°.
  • the HLB (hydrophilic lipophilic balance) value for a surfactant hydrophilic material is generally greater than 10, usually greater than 20, and preferably greater than 30.
  • the HLB value may lie in the range 25 to 55, preferably 30 to 50.
  • Figure 1 is a cross-sectional elevation of a controlled release device in the form of a capsule consisting of a body, hydrogel plug and cap.
  • the capsule is more particularly described in our published patent specification W094/09745, and comprises a male member in the form of a plug 2 formed of a hydrogel material, inserted in neck 4 of female body 6.
  • the capsule is closed with a cap 8.
  • the body 6 is, for example, of overall length about 18mm and comprises a cylindrical main portion 10 and closed end 12.
  • the main body narrows to the neck portion 4 at a shoulder region 5.
  • the neck portion is substantially cylindrical (internal diameter when coated is about 6.7mm) so as to receive the male plug 2 with a close tolerance.
  • the neck portion then flares out to a flared mouth portion 14 which has an opening 15 of a diameter substantially the same as the diameter of the main body portion 10.
  • 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 above, level with or below the upper end of the capsule body.
  • the capsule is then sealed with the cap 8 which is provided with detents 18 which clip under the rim of the flared mouth portion thereby locking the cap in place.
  • the cap has a cylindrical skirt portion 9 which extends down to the open end of the cap.
  • the lower end of the skirt portion extends downwardly past the shoulder 5 of the body and encloses an upper part of the body with only a small clearance. This helps to stabilise the cap and prevent it tilting from side to side. It also allows the cap to be sealed to the body by means of an annular band passing over the junction therebetween.
  • the mole ratios were PEG 8000 (1 mole) , hexanetriol (1.2 moles) , Desmodur W f2.3 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 35°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 tubular polytetrafluoroethylene 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 were 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.
  • the hydrogel rod was then cut into plugs, each generally of a nominal length 4mm.
  • a gelatin capsule body as shown in Figure 1 was coated with a water-insoluble water-impermeable ethyl cellulose coating in the following manner.
  • a batch of gelatin capsule bodies were introduced into an Accelacota spray coating machine (Manesty Machines Ltd., U.K.).
  • the spray coating machine was operated according to the manufacturer's instructions.
  • a solution of ethyl cellulose (E100) in a mixture of isopropyl alcohol and acetone (50:50 by wt.) was sprayed onto the capsule bodies until an ethyl cellulose coating representing an 80% weight gain had been deposited.
  • the inlet air temperature to the coating machine was 45°C and the outlet air temperature 40°C.
  • the drum speed was 9.5rpm.
  • the ethyl cellulose coated gelatin bodies were then stored for future use.
  • the ethyl cellulose coating covers the entire outer surface of the capsule body and extends part way down the interior surface of the capsule body, so that all regions of the body which in use are in contact with aqueous liquid when the hydrogel plug is installed, are coated with the water impermeable ethyl cellulose coating.
  • Example 1 50g of ethylcellulose coated bodies produced according to Example 1 were added to a coating machine of the type given below and heated for 10 minutes prior to spray application of the coating solution. Spraying was continued until the required weight loading was achieved.
  • the Table below shows the equipment used, together with the process conditions recorded, for each batch of coated bodies investigated in the determination of emptying rate and air bubble formation studies.
  • IPA is an abbreviation for isopropyl alcohol.
  • HPMC is an abbreviation for hydroxypropylmethyl cellulose.
  • Each capsule body was filled with a 200mg slug of Low Substituted Hydroxy Propyl Cellulose (LH21) powder. This material expands in contact with water. Then each capsule was fitted with a 3.00mm long hydrogel plug produced according to Example 1. It was only possible to video film a maximum of 10 capsules at any one time. Therefore the experiment was repeated until all six coatings had been investigated.
  • LH21 Low Substituted Hydroxy Propyl Cellulose
  • Example 4 indicated that incorporation of a top layer of hydrophilic material by conventional spray coating techniques decreased significantly the incidence of air bubble retention upon plug ejection. This experiment aimed to quantify the improvement seen in emptying of the fill material from the capsule body.
  • Each capsule body was filled with lOOmg of LH21 powder. This was compacted. A placebo tablet was placed on top. The LH21 powder is intended to expand in contact with water and thereby to eject the tablet from the body.
  • the devices were fitted with a 2.5mm long plug of a hydrogel produced in Example 1 which protruded 1.5mm out of the neck of the oody, and gave a conveniently short plug ejection time for direct observation. They were then placed on a plastic holder and fixed onto the base of a glass tank. Water
  • the ethyl cellulose coated comparison bodies did not empty at all.
  • the ejected plugs remained sitting on the capsule bodies, vith air bubbles located in the neck of the body. Even upon physical removal of the plug no tablet emptying was seen.
  • the third non-ionic surfactant screened (Myrj 53, a fatty-acid ethoxylate) gave a mean advancing angle of 69.9 and also performed significantly better (55% of capsules tested emptied) in the in-vitro emptying test.
  • anionic eg sodium lauryl sulphate
  • non- ionic eg alcohol ethoxylates
  • hydrophilicity of surfactants varies and they are assigned HLB values accordingly. High HLB values correspond to more hydrophilic materials. In general anionic and cationic surfactants have higher HLB values than non-ionic surfactants.
  • non-ionic surfactant group an example of the three main types were chosen, ie Brij 72 (an alcohol ethoxylate ie polyoxyl 2 stearyl ether) , Myrj 53 (a fatty-acid ethoxylate ie polyoxy 50 stearate) and Synperonic F127 (a Poloxamer ie a polyoxyethylene polyoxypropylene copolymer) .
  • Gelatin capsule bodies which had been previously coated with a water-impermeable ethylcellulose coating were top-coated with a hydrophilic coating as follows.
  • a Strea 1 Aeromatic Aerocoater was used to top ⁇ coat the capsule bodies.
  • the following spraying parameters were used for each batch: Atomising Pressure 1.0 bar
  • Table 1 gives the formulation details of each coating solution and the mean weight loading of the applied film.
  • EXAMPLE 8 Contact angle measurement of films cast from eacn of the top-coat formulations onto microscope cover-slips.
  • Example 7 The in-vitro emptying experiment of Example 7 gave an indication as to whicn film/surfactant combination would give suitable performance. HLB (hydrophilic lipophilic balance) values could be used to predict which surfactants were most hydrophilic; however, contact angle measurement gives a numerical value which would allow us to rank film/surfactant combinations. The measurement of the advancing angle using a contact angle measuring technique provides a better understanding of which film/surfactant combinations were most suitable.
  • the cover-slip was submerged in the solution using tweezers. The solvent was then evaporated by passing warm air over the cover-slip. The process was repeated a further three times to ensure a film was deposited on both sides of the cover-slip. Five examples from each film-type were prepared.
  • the samples were then analysed for contact angle using water as the liquid medium.
  • the technique used to measure contact angle was a standard Wilhelmy plate technique, using a Cahn DCA apparatus.
  • the plate is suspended from a microbalance and the liquid raised using a motorised platform.
  • the force is recorded as a function of distance and the contact angle calculated from the force at zero depth of immersion (by an extrapolation procedure) .
  • the force measured is a function of surface tension, plate perimeter and contact angle.
  • hydrophilic top-coat improves spread of water on the capsule surface and hence promotes expulsion of capsule contents when ;ompared to the standard ethylcellulose only coating.

Landscapes

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

Abstract

Un corps de capsule (6), destiné à un dispositif à libération modulée, comprend un revêtement d'un matériau hydrophile présent au moins dans la zone du col (4) adjacente à son ouverture (15). Ce matériau hydrophile peut être un matériau et/ou un agent tensioactif destiné à former une pellicule. Son objet est de faciliter la pénétration de l'eau dans le corps de capsule pour libérer une substance pharmaceutique qui y est contenue, une fois qu'un tampon d'hydrogel (2) a gonflé et s'est dégagé du corps après une durée prédéterminée. Un revêtement hydrophile préféré est constitué d'un mélange d'éthyle cellulose et de docusate de sodium.
EP95928589A 1994-08-20 1995-08-18 Dispositif hydrophile a liberation modulee Withdrawn EP0776196A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9416902A GB9416902D0 (en) 1994-08-20 1994-08-20 Hydrophilic controlled release device
GB9416902 1994-08-20
PCT/GB1995/001962 WO1996005812A1 (fr) 1994-08-20 1995-08-18 Dispositif hydrophile a liberation modulee

Publications (1)

Publication Number Publication Date
EP0776196A1 true EP0776196A1 (fr) 1997-06-04

Family

ID=10760188

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95928589A Withdrawn EP0776196A1 (fr) 1994-08-20 1995-08-18 Dispositif hydrophile a liberation modulee

Country Status (5)

Country Link
EP (1) EP0776196A1 (fr)
JP (1) JPH10504558A (fr)
AU (1) AU3230395A (fr)
GB (1) GB9416902D0 (fr)
WO (1) WO1996005812A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1073093C (zh) * 1997-03-10 2001-10-17 巴斯福股份公司 糖精－5－羰基环己烷－1,3,5－三酮衍生物、其制备及作为除草剂的应用
DE19923817A1 (de) * 1999-05-18 2000-11-23 Roland Bodmeier Kapsel mit kontrollierter Wirkstofffreisetzung
US7115565B2 (en) 2001-01-18 2006-10-03 Pharmacia & Upjohn Company Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability
US20070128251A1 (en) * 2005-12-07 2007-06-07 Piedmont Pharmaceuticals, Inc. Process for manufacturing chewable dosage forms for drug delivery and products thereof
US9550050B2 (en) 2006-09-25 2017-01-24 MEDIMETRICS Personalized Drug Delivery B.V. Medicament delivery apparatus

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5842723U (ja) * 1981-09-16 1983-03-22 株式会社日本自動車部品総合研究所 内燃機関用ノツキング検出器
US4539060A (en) * 1983-02-18 1985-09-03 Warner-Lambert Company Apparatus and method of sealing capsules
GB9009331D0 (en) * 1990-04-26 1990-06-20 Polysystems Limited Sustained release
GB9223172D0 (en) * 1992-11-05 1992-12-16 Scherer Corp R P Capsule construction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9605812A1 *

Also Published As

Publication number Publication date
AU3230395A (en) 1996-03-14
WO1996005812A1 (fr) 1996-02-29
GB9416902D0 (en) 1994-10-12
JPH10504558A (ja) 1998-05-06

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