WO1995017173A1 - Medicament expulse par un gaz hors d'un dispositif de liberation pris par voie orale - Google Patents

Medicament expulse par un gaz hors d'un dispositif de liberation pris par voie orale Download PDF

Info

Publication number
WO1995017173A1
WO1995017173A1 PCT/GB1994/002794 GB9402794W WO9517173A1 WO 1995017173 A1 WO1995017173 A1 WO 1995017173A1 GB 9402794 W GB9402794 W GB 9402794W WO 9517173 A1 WO9517173 A1 WO 9517173A1
Authority
WO
WIPO (PCT)
Prior art keywords
excipient
water
aqueous medium
plug
coating
Prior art date
Application number
PCT/GB1994/002794
Other languages
English (en)
Inventor
Howard Norman Ernest Stevens
Julie Stephanie Binns
Marilyn Irene Guy
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
Publication of WO1995017173A1 publication Critical patent/WO1995017173A1/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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds

Definitions

  • the present invention relates to the expulsion of a substance to be delivered, for example a pharmaceutically active material, from a hollow body of a delivery device, such as a capsule.
  • a delivery device such as a capsule.
  • the present invention relates to a controlled release device for delivering the substance to a patient at a chosen time (e.g. 2 to 10 hours) following administration.
  • the device is useful to allow administration of active material at a predetermined point as the capsule passes through the gastro-intestinal tract, for example in the colon.
  • Patent specification 092/13521 (Alza Corporation) describes fluid-imbibing dispensing devices for delayed delivery of an active agent, which include an expansion means which absorbs fluid from a surrounding environment.
  • the dispensing device comprises a housing having first and second wall sections telescopically engaged with each other, particularly a capsule having a hollow cap and a hollow body; either the cap or the body is in the form of a male section fitted inside the open end of the other female section.
  • the expansion means is contained within the device and expands as it absorbs fluid, forcing apart the two sections of the device.
  • the expansion means may be a swellable polymer or an osmotic formulation which swells as it absorbs fluid.
  • one of the wall sections adjacent to the expansion means is fluid-permeable. After the sections are disengaged, fluid enters the device and comes into contact with the active agent contained within the device, thereby dispensing the active agent into the fluid.
  • the success of the device depends not only on the release of the male member at the chosen time, but also on the successful emptying of the contents of the capsule shortly thereafter, so that they become absorbed into the patient's system at the required time.
  • the emptying of the capsule requires either an active material which is very soluble in water or an adequate supply of aqueous medium in order to flush the contents from the capsule.
  • the water content is low, so that emptying of the capsule may be inhibited.
  • the present invention provides a delivery device for delivering a substance, which comprises a hollow body containing the substance to be delivered, together with an excipient whose volume expands in contact with an aqueous environment such as to expel the substance from the body.
  • the expansion of the excipient acts to positively expel the substance from the body, such as to provide reproducible delivery times.
  • the excipient is a material which generates a gas when it comes into contact with the aqueous medium.
  • Suitable systems are known in the art, and generally comprise a first component in the form of a pharmaceutically acceptable carbonate or bicarbonate, together with a second component in the form of a pharmaceutically acceptable acid.
  • the acid is usually an organic acid in solid form, such as citric acid or adipic acid.
  • the first and second components together constitute an effervescent mixture. In the presence of water, at least the acid dissolves and comes into contact with the carbonate or bicarbonate, thereby releasing carbon dioxide.
  • the device further comprises a male member engaged with a neck portion of the (female) body, the device including a water-swellable material which swells so as to disengage the female body upon exposure of the device to the aqueous medium, and thereby allows the aqueous medium to come into contact with the expandible excipient within the female body.
  • the male member is in the form of a male plug formed of the water-swellable material, preferably a hydrogel, engaged within the neck of the female body.
  • the construction, chemical composition and fitting of the male hydrogel plug determines the time taken for the hydrogel plug to swell and become disengaged from the female hollow body (i.e. the "pulse" time) .
  • hydrogel materials are mentioned in W090J09168 and include poly(hydroxyethyl-methacrylate) , poly(N-vinyl-pyrrolidone) , and polyurethanes.
  • a particularly preferred class of hydrogels are those cross-linked hydrophilic polymers comprising polyethylene oxide residues. Chemical cross-linking may be effected in known manner. Where the hydrophilic polymer comprises functional groups which comprise an active hydrogen atom, chemical cross-linking may be effected by means of di-or-polyisocyanates.
  • the polyethylene oxide residues have a number average molecular weight greater than 1500, preferably greater than 3,000, and most preferably from 4,000 to 12,000.
  • Particularly preferred polyurethane materials are formed by polymerising a polyethylene glycol, with a Cg-C 10 alkanetriol, and a diisocyanate.
  • the water-swellable hydrogel has a swelling capacity of greater than 50%, particularly greater than 100%, preferably greater than 200% and advantageously more than 300%. This percentage swellability represents the percentage increase in weight over and above the original weight.
  • the walls of the female body may be formed from a wide variety of materials, such as disclosed in W090/09168. They may be of homogenous constructions or they may be laminated. Examples of materials suitable for use in the construction of the body include polyethylene, polypropylene, poly(methylmethacrylate) , polyvinyl chloride, polystyrene, polyurethanes. polytetrafluoroethylene, nylons, polyformaldehydes, polyesters, cellulose acetate and nitro cellulose.
  • a preferred construction uses a water-impermeable coating to cover the exterior of a body formed from a water soluble material.
  • the coating may conveniently be formed by dipping a body in a solution of a material which forms a layer which is impermeable to water.
  • the body may be spray-coated.
  • a preferred class of bodies are conventional hard gelatin or starch capsule bodies coated with a solution of polyvinyl chloride or polyvinyl acetate copolymer, or an ethyl cellulose solution.
  • the male member is a hollow member closed at one end, whose opposite open end engages within the neck of the female body.
  • a water swellable material is provided within the device which serves to disengage the female member after a predetermined time, by forcing the male member and the female body apart as the material swells in the presence of water.
  • the swellable material inside the device may be an osmagent or an osmopolyer. Such an arrangement is disclosed in W092/13521.
  • a portion of the wall of the device adjacent thereto is preferably semipermeable; that is to say it is permeable to the passage of water into the device but impermeable to release of other substances from within the device.
  • the effervescent mixture in the hollow body may be sensitive to the presence of water vapour, which is a problem particularly where the body may have some limited permeability to water vapour, such as in the case of coated hard gelatin capsules. This may lead to premature gas generation before the substance is intended to be expelled.
  • a water-vapour impermeable coating for example a hydrophobic coating, such as a wax.
  • Suitable waxes include food grade materials, such as Cutina Suppocire and cetyl ester wax.
  • one or both of the components of the effervescent mixture may be granulated or pelleted.
  • the coated effervescent mixture itself may be formed into a tablet.
  • the coating material is a material which is solid at ambient temperature but which melts at body temperature of 37°C.
  • the wax Suppocire AP has a melting point of approximately 34°C, which is below body temperature.
  • a water-soluble emulsifying agent is included in the coating formulation, higher melting point waxes can be also employed, such as cetyl ester wax (melting point 43° to 45°C) and hydrogenated castor oil waxes (e.g. Cutina HR, melting point 85 to 88°C) .
  • the water-soluble emulsifying agent is for example sodium docusate (available under the trade name Alcopol) .
  • the coating formulation could include a wetting agent, such as sodium stearate, sodium lauryl sulphate, dioctyl sodium sulphosuccinate, a Tween surfactant, a poloxamer such as poloxamer 188, and glycerol monostearate.
  • a wetting agent such as sodium stearate, sodium lauryl sulphate, dioctyl sodium sulphosuccinate, a Tween surfactant, a poloxamer such as poloxamer 188, and glycerol monostearate.
  • sugars may be included in the coating formulation so as to improve flow properties and also to aid wetting.
  • the sugar may for example be sorbitol, lactose or sucrose.
  • the coating is applied in an amount of 10-200%, preferably 50-100% by weight of the carbonate or bicarbonate.
  • the coating composition may be dissolved in a solvent.
  • Application to the solid excipient may be by pouring, spraying or pan coating the excipient.
  • the solvent may be a suitable food grade solvent, such as isopropyl alcohol. The solvent is then evaporated off.
  • An alternative way of preventing premature gas generation involves including an inert water absorbing agent, such as silica gel, in the effervescent formulation in order to absorb any water vapour present.
  • an inert water absorbing agent such as silica gel
  • premature gas generation may force the male member (e.g. a hydrogel plug) out of the female body too early, thereby leading to reduced and unreliable pulse times and delivery times. Moreover, the male member may be ejected with an unacceptable force. Secondly, premature gas generation may use up the effervescent materials, leading to reduced availability later when the substance is intended to be expelled.
  • the male member e.g. a hydrogel plug
  • a further aspect of the present invention relates to a method of expelling a substance to be delivered from a hollow body, which comprises providing said substance within the hollow body together with an excipient whose volume expands in contact with an aqueous environment such as to expel the substance.
  • Figure 1 is a cross section to an enlarged scale of a delivery device according to the present invention.
  • the device is in the form of a capsule comprising a male plug 2 formed of a hydrogel material inserted in neck 4 of female body 6.
  • the device is closed with a cap 8 of water-soluble material.
  • the male plug 2 is formed of a hydrogel material, such as disclosed in W090/09168.
  • the hydrogel may be formed of a cross-linked polyurethane formed as described in Example 1.
  • the male plug is usually inserted so that the upper end of the plug is proud of, level with or recessed below the upper end of the neck 4.
  • the cap 8 is formed of a water-soluble material (e.g. is a hard gelatin cap) , which dissolves quickly in the stomach after administration to a patient.
  • the body 6 is formed of a water-insoluble material, which may be a water-insoluble plastics material such as low density polyethylene, or may be a hard gelatin body coated with a water-impermeable coating (such as disclosed in W090/09168) .
  • a lower layer 12 of an effervescent mixture is contained within the capsule body 6. Positioned above this, is an upper layer 10 of active material which is to be expelled from the body.
  • the active material may comprise a pharmaceutically acceptable carrier if required.
  • the aqueous medium in the gastro-intestinal tract quickly dissolves the water-soluble cap. Water is then absorbed into the hydrogel plug 2, which swells and is expelled from the body 6 after a predetermined time interval (for example 0.5 to 12 hours) . Thereafter, the aqueous medium within the gastro-intestinal tract enters the capsule body and causes the effervescent mixture to effervesce and release carbon dioxide gas. This foaming mixture expels the contents of the hollow capsule body including the active layer 10 and delivers the contents into the gastro-intestinal tract.
  • the time for expulsion of the contents of the body 6 after expulsion of the hydrogel plug is preferably short, for example 2 to 20 minutes, compared to the pulse time for disengagement of the plug.
  • the mixture at 85°C was then mixed with the Desmodur W by pumping into a mixer rotating at 1500 revolutions per minute.
  • Molten polymer at about 80°C was then dispensed into tubuler polytetrafluorethylene moulds 25cm long and internal diameter about 6.7mm under a vacuum of less than 50 millibars. Curing took place at 95°C for 4 hours in a fan equipped oven. The hydrogel polymer rods were then allowed to cool.
  • the hydrogel rods are washed by immersion in a circulating stream of water containing butylated hydroxy anisole (BHA) as a stabiliser.
  • BHA butylated hydroxy anisole
  • the swelling factor is defined as (Ws-Wd) JWd x 100, where Ws is the swollen weight and Wd is the dry weight.
  • the hydrogels were found to have a swelling factor of 270 ⁇ 25.
  • Suppocire AP was dissolved in isopropanol and mixed with sodium carbonate, and dried under vacuum for 24 to 48 hours to form granules.
  • the Suppocire coated sodium bicarbonate was then blended with the other raw materials as set out in Table l below.
  • the Table indicates the emptying time for effervescent formulations placed in open-ended low density polyethylene capsules, after the capsules were placed in a bath containing water and equipped with a stirrer (50 rpm) .
  • Adipic acid-containing formulations are given in Table 4 below. These were filled into open-ended polyethylene capsule bodies and the emptying times measured as in Example 1.
  • Lactose 135 135 115 125 135 Lactose 135 135 115 125 135
  • sucrose was granulated with a solution of dioctyl sodium sulphosuccinate and oven dried at 50°C.
  • the Cutina HR was dissolved in isopropyl alcohol, mixed with sodium bicarbonate, screened and dried at 50°C. The materials were then mixed together.

Landscapes

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

Abstract

Ce dispositif de libération destiné à libérer un principe actif (10) à un moment prédéterminé (par exemple 0,5 à 12 heures) après son administration à un patient, comprend un corps femelle creux (2) doté d'un bouchon (6) formé d'un matériau hydrogel et placé dans le col (4) dudit corps creux. Le bouchon gonfle au contact d'un milieu aqueux (par exemple le fluide gastro-intestinal) et se dégage du corps creux à un moment prédéterminé. Un excipient (12) dont le volume gonfle au contact du milieu aqueux est placé dans le corps femelle afin d'expulser rapidement et totalement hors dudit corps le principe actif dans le milieu aqueux, après dégagement du bouchon. L'excipient expansible est un matériau qui génère un gaz lorsqu'il est mis en contact avec un milieu aqueux, tel qu'un mélange d'un carbonate ou bicarbonate et d'un acide.
PCT/GB1994/002794 1993-12-23 1994-12-22 Medicament expulse par un gaz hors d'un dispositif de liberation pris par voie orale WO1995017173A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB939326334A GB9326334D0 (en) 1993-12-23 1993-12-23 Expelling substance

Publications (1)

Publication Number Publication Date
WO1995017173A1 true WO1995017173A1 (fr) 1995-06-29

Family

ID=10747123

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1994/002794 WO1995017173A1 (fr) 1993-12-23 1994-12-22 Medicament expulse par un gaz hors d'un dispositif de liberation pris par voie orale

Country Status (2)

Country Link
GB (1) GB9326334D0 (fr)
WO (1) WO1995017173A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0250083A2 (fr) * 1986-06-19 1987-12-23 Alza Corporation Forme de dosage avec des moyens pour commander le taux de formation de gaz

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0250083A2 (fr) * 1986-06-19 1987-12-23 Alza Corporation Forme de dosage avec des moyens pour commander le taux de formation de gaz

Also Published As

Publication number Publication date
GB9326334D0 (en) 1994-02-23

Similar Documents

Publication Publication Date Title
US5827538A (en) Osmotic devices having vapor-permeable coatings
JP2862222B2 (ja) ｐＨ作動性浸透破裂放出用製剤
EP0384646B1 (fr) Dispositif de délivrance d'un principe actif
US4207890A (en) Drug-dispensing device and method
US5458887A (en) Controlled release tablet formulation
US4475916A (en) Osmotic drug delivery system
EP0010876B1 (fr) Dispositif agissant par osmose pour libérer des substances
EP0180708B1 (fr) Dispositif osmotique pour libérer une substance active
CA2689049C (fr) Systeme de retention gastrique renfermant un corps d'alginate
JPS6244248A (ja) 家畜用デイスペンサ
SK49389A3 (en) Floating system for oral therapy
JPS6239519A (ja) 有効剤を投与するための速度制御投与装置
US5897874A (en) Expulsion of material from a delivery device
US5342624A (en) Dispensing device
ZA200500834B (en) Oral dosage form comprising a liquid active agent formulation and controlling release thereof by an expandable osmotic composition
IE62747B1 (en) Controlled porosity osmotic pump.
WO1995017173A1 (fr) Medicament expulse par un gaz hors d'un dispositif de liberation pris par voie orale
WO1995017171A1 (fr) Dispositif de liberation permettant une liberation retardee d'un principe actif contenant un agent de solubilisation
WO1995010262A1 (fr) Dispositif permettant une liberation regulee de liquides
WO1996005812A1 (fr) Dispositif hydrophile a liberation modulee
WO1995013056A1 (fr) Dispositif de liberation
US20040062799A1 (en) Therapeutic composition and delivery system for administering drug

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase