Modified-Release
`Drug Delivery Technology
`Second Edition
`Volume 1
`
`edited by
`Michael J. Rathbone
`InterAg
`Hamilton, New Zealand
`Jonathan Hadgraft
`University of London
`London, UK
`Michael S. Roberts
`University of Queensland
`Brisbane, Australia
`Majella E. Lane
`University of London
`London, UK
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`CRC Press
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`30
`PulsincapTM and Hydrophilic Sandwich
`Capsules: Innovative Time-Delayed Oral
`Drug Delivery Technologies
`
`H. N. E. Stevens
`Department of Pharmaceutical Sciences, University of Strathclyde,
`Glasgow, Scotland
`
`INTRODUCTION
`
`Chronopharmaceutical drug delivery (1) discussed the delivery of drugs in
`accordance with the circadian rhythms of the disease. The identification
`of a specific time-dependent “trigger” capable of provoking drug release
`from an oral formulation after a pre-determined time interval represents a
`significant challenge to the pharmaceutical formulator.
`
`PULSINCAPTM TECHNOLOGIES
`
`Three variants on a capsule theme have been developed that trace their
`origins back to PolySystems Ltd, a small Scottish company in the late 1980s.
`The first concept consisted of a device based on the separation of a plug
`from an insoluble capsule body which was first described by Rashid (2). This
`formulation, which was described in the patent literature, comprised a water
`permeable body (Fig. 1) prepared from a water swellable hydrogel cross-
`linked polyethylene glycol (PEG) polymer. Depending on their composition,
`such polymers have the capacity to swell significantly, but in a controlled
`manner, in aqueous media. A swelling agent (powdered high-swelling poly-
`mer) mixed with drug, was filled into the internal cavity of Rashid’s
`molded capsule body and a plug (also of high-swelling polymer) was used to
`seal the contents into the internal cavity. The rate at which water diffused
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`Stevens
`
`Thick-walled,
`permeable,
`
`Plug,
`cross-linked hydrogel
`
`cross-linked hydrogel
`
`Swelling agent
`(cross-linked hydrogel)
`
`Drug formulation
`
`Figure 1
`
`Pulsatile hydrogel capsule. Source: From Ref.2.
`
`into the core was controlled by the hydrogel composition and wall thickness
`of the capsule. The delay period prior to drug release was defined by the time
`taken forfluid to diffuse through the wall. When fluid came into contact with
`the capsule contents,
`the high-swelling polymer absorbed water rapidly,
`swelled and caused internal pressure to be generated inside the capsule. This
`pressure caused the plug to be expelled from the neck of the capsule and drug
`to be released in a pulsatile manner. Optimization of the construction of the
`components and the chemistry of the hydrogel polymers enabled time-delays
`to be controlled reproducibly.
`A manually prepared prototype formulation with a 5-hour lag time
`was the subject of a pharmacokinetic study in man designed to release
`captopril in the colon of the fasted volunteers. Scintigraphic observations
`confirmed that drug was released from the capsule at the target site, how-
`ever, pharmacokinetic analysis confirmed that minimal absorption had
`taken place from the colon (3).
`Molding the thermosetting hydrogel polymers required for the cap-
`sule body was a very complex process that did not lend itself to industrial
`scale-up. Further developments of this technology, now more widely
`referred to as Pulsincap™, were undertaken and improved devices were
`described in the patent
`literature (4). Polysystems was acquired by RP
`Scherer Corporation in 1990 and the Pulsincap technology was then
`developed by Scherer DDS Ltd. This second generation Pulsincap device
`wasless complex than Rashid’s earlier capsule and the hydrogel body of the
`earlier formulation was nowreplaced by a gelatin capsule, film-coated with
`ethyl cellulose to render it impermeable (Fig. 2). The link to hydrogel pol-
`ymer chemistry was retained and a molded hydrogel plug was used to seal
`the drug contents into the capsule body. In the presence of fluid, the plug
`swelled at a controlled rate that was independentof the nature or pH ofthe
`medium (5).
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`Pulsincap™ and Hydrophilic Sandwich Capsules
`
`339
`
`Water impermeable,
`ethyl cellulose-coated
`gelatin capsule
`
`
` Swellable,
`
`Soluble gelatin cap
`
`hydrogel plug
`
`(A)
`
`(C)
`
`Expulsion agent
`
`Drug formulation
`
`Gelatin cap dissolves,
`plug swells in contact
`with fluid and starts to
`pull out of capsule
`
`Swollen plug ejects,
`fluid enters capsule,
`expulsion agent swells
`and drug is expelled
`
`Figure 2. Pulsincap™ delivery system. Source: From Ref.4.
`
`As it swelled, the plug developed a frustro-conical shape and slowly
`pulled itself out of the capsule. The length of the plug and its insertion
`distance into the capsule controlled the pulse timereliably.
`This second generation Pulsincap formulation has been studied in
`numerous humanvolunteerstudies(e.g., (6,7)) and was well tolerated in man
`(8). In order to effect complete drug release from the capsule following plug
`ejection, an active expulsion system was employedto rapidly and completely
`expel the contents from the capsule, as demonstrated with delivery ofsal-
`butamol to human volunteers, where the expulsion system low-substituted
`hydroxypropylcellulose (LH-21®, Shin-Etsu) was employed (9,10).
`Due to the fact that the mechanism of action was controlled by the
`plug sliding out of the capsule, a significant factor for the correct operation
`of Pulsincap wasthe tightness of fit of the hydrogel plug in the capsule. If
`the fit of the plug wastoo slack it ejected prematurely, whereas whenitfitted
`too tightly, drug was released erratically (11). In order to respect the very
`tight dimensional specifications demanded for predictable operation, each
`plug wassubjected to three-dimensional measurementusing laser gauges. As
`a result of the cost implication of this requirement, the delivery system was
`never adopted for large scale human healthcare applications. However, a
`low volume diagnostic test kit based on Pulsincap releasing nutrient com-
`ponents into a microbial test medium after a 6-hour lag time, was com-
`mercialized in 1997 (SprintSalmonella™, Oxoid Ltd, Basingstoke, UK).
`More recent studies have been undertaken on a further simplified
`adaptation of the technology. Now working at Strathclyde University
`Stevens et al. (12) and Rosset al. (13) eliminated reliance on hydrogel
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`
`Stevens
`
`Waterimpermeable,
`
`Soluble gelatin cap
`
`(A)
`
`Expulsion agent
`
`Drug formulation
`
`Erodible plug
`
`os
`a
`Y,
`
`,
`
`¢
`
`ethyl cellulose-coated gelatincapsule
`77 &4Baoe
`
`
`Gelatin cap dissolves,
`plug startstoerode
`in contact with fluid
`
`Plug fully eroded,
`fluid enters capsule
`and drug is released
`(C)
`
`(B)
`
`Figure 3. Erodible plug time-delayed capsule. Source: From Ref. 12.
`
`polymers and developed a Pulsincap formulation that employed a simple
`erodible compressed tablet in place of the swelling hydrogel plug (Fig. 3).
`Since the tablet eroded in place, it did not moverelative to the capsule body
`and this factor overcame the need for the precise dimensional tolerances
`between plug and capsule required by the sliding mechanism of the plug in
`the earlier Pulsincap formulations.
`A range of erodible tablet formulations were studied using ethyl
`cellulose-coated gelatin capsule bodies. It was shownthat controllable time-
`delayed release of propranolol could be achieved with pulse-time being
`determined by either plug composition orits thickness. Rosset al. (13) again
`utilized low-substituted hydroxypropylcellulose (LH-21°, Shin-Etsu) as a
`swellable expulsion system and achieved release of propranolol over a
`controllable 2 10 hour range using erodible tablet plugs compressed from
`mixed lactose and HPMC (Methocel®, DOW)excipients.
`Krogel and Bodmeier(14) similarly studied the application of erodible
`plugs fitted in plastic capsules using formulations based on either com-
`pressed tablets or congealed semi-solid materials. Release of chlorphenir-
`amine after time-delays was obtained by manipulating plug composition or
`weight.
`
`HYDROPHILIC SANDWICH CAPSULE
`
`In an attempt to develop a simple, time-delayed probe capsule, Stevens
`et al.
`(15) devised a manually assembled delivery system based on a
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`341
`
`Outer gelatin capsule
`
`(size 000 or 0)
`
`‘Sandwich layer
`hydrophilic polymer
`(HPMC)
`
`Inner gelatin capsule
`containing drug
`(size O or 4)
`
`Figure 4 The hydrophilic sandwich capsule. Source: From Ref. 15.
`
`capsule-within-a capsule, in which the intercapsular space wasfilled with a
`layer of hydrophilic polymer (HPMC). This effectively created a “hydro-
`philic sandwich” (HS) between the two gelatin capsules. When the outer
`capsule dissolved, the sandwich of HPMCformeda gel barrier layer which
`provided a time-delay before fluid could enter the inner capsule and cause
`drug release. The time-delay was controlled by the molecular weight of the
`polymer and could be further manipulated by the inclusion of a soluble
`filler, e.g., lactose, in the hydrophilic layer (Fig. 4).
`The HS capsule was studied in two configurations, either with an
`external size 000 capsule and an internal size 0, or a “mini HS,” in which the
`external capsule wassize 0 and the internal capsule was size 4. Soutaret al.
`(16) employed a gastroresistant version of the larger HS capsule in a cohort
`of 13 volunteers to deliver 500mg paracetamol to the ileocecal junction/
`proximal colon. Absorbed drug was monitored using salivary analysis and a
`mean Tyax Value of 7.9 hours (SD + 0.96) was observed.
`
`CONCLUDING REMARKS
`
`Pulsed drug delivery using systems based on Pulsincap technology and deri-
`vatives has been demonstrated in the clinic using scintigraphy. Current
`research is focused on providing a readily adaptable configuration whose
`release characteristics in vivo can accurately be reflected in compedial
`in vitro tests. Results so far are extremely encouraging with good concor-
`dance in healthy volunteers.
`
`REFERENCES
`
`1. Stevens HNE. Chronopharmaceutical drug delivery. J Pharm Pharmacol 1998;
`50:S5.
`2. Rashid A. Dispensing device. EP 0 384 642, 1990.
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`342
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`Stevens
`
`3. Wilding IR, Davis SS, Bakhshaee M, Stevens HNE, Sparrow RA, Brennan J.
`Gastrointestinal transit and systemic absorption of captopril from a pulsed-
`release formulation. Pharm Res 1992; 9:654 7.
`4. McNeill ME, Rashid A, Stevens HNE. Drug dispensing device. GB patent, 2
`230 442, 1993.
`5. Binns JS, Bakhshaee M, Miller CJ, Stevens HNE. Application of a pH inde-
`pendent PEG based hydrogel to afford pulsatile delivery. Proc Int Symp
`Control Rel Bioact Mater 1993; 20:226 7.
`6. Bakhshaee M, Binns JS, Stevens HNE, Miller CJ. Pulsatile drug delivery to the
`colon monitored by gamma scintigraphy. Pharm Res 1992; 9(Suppl):F230.
`7. Hebden JM, Wilson CG, Spiller RC, et al. Regional differences in quinine
`absorption from the undisturbed human colon assessed using a timed release
`delivery system. Pharm Res 1999; 16:1087 92.
`8. Binns JS, Stevens HNE, McEwen J, et al. The tolerability of multiple oral doses
`of Pulsincap capsules in healthy volunteers. J Control Release 1996; 38:151 8.
`9. Stevens HNE, Binns JS, Guy MI. Drug expelled from oral delivery device by
`gas. International Patent Application WO 95/17173, 1995.
`10. Stevens HNE, Rashid A, Bakhshaee M, Binns JS, Miller CJ. Expulsion of
`material from a delivery device. US patent 5 897 874, 1999.
`11. Hegarty M, Atkins G. Controlled release device. International patent appli-
`cation WO 95/10263A1, 1995.
`12. Stevens HNE, Rashid A, Bakhshaee M. Drug dispensing device. US patent, 5
`474 784, 1995.
`13. Ross AC, MacRae RJ, Walther M, Stevens HNE. Chronopharmaceutical drug
`delivery from a pulsatile capsule device based on programmable erosion. J
`Pharm Pharmacol 2000; 52:903 9.
`14. Kro¨ gel I, Bodmeier R. Pulsatile drug release from an insoluble capsule body
`controlled by an insoluble plug. Pharm Res 1998; 15:474 81.
`15. Stevens HNE, Ross AC, Johnson JR. The hydrophilic sandwich (HS) capsule:
`a convenient time-delayed oral probe device. J Pharm Pharmac 2000; 52:S41.
`16. Soutar S, O’Mahony B, Bakhshaee M, et al. Pulsed release of paracetamol from
`the Hydrophilic Sandwich (HS) capsule. Proc Int Symp Control Rel Bioact
`Mater 2001; 28:790 1.
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