`
`Exhibit 1009
`
`S. S. Davis, The Design and Evaluation of
`Controlled Release Systems for the
`Gastrointestinal Tract, 2 J. CONTROLLED
`RELEASE 27 (1985) (“Davis 1985”)
`
`

`
`Journal of Controlled Reteose,
`27-38
`2 (1985)
`Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands
`
`27
`
`THE DESIGN AND EVALUATION OF CONTROLLED RELEASE SYSTEMS FOR THE
`GASTROINTESTINAL
`TRACT*
`
`S.S. Davis
`Department
`of Pharmacy, University of #orti~gh~m,
`
`University Park, ~ottj~gham
`
`NG7 2RD
`
`[Great Britain1
`
`tract requires knowl-
`for the gastrointestinal
`systems
`The design and evaluation of delivery
`the drug,
`the delivery
`system and
`the destination
`edge about
`three
`inter-related
`topics,
`intended,
`preformulation
`data describing
`the physi~o~hemica~
`characteristics
`of a drug
`molecule need
`to be considered
`in relation
`to known physiological
`variables such asgastro-
`intestinal pH gradients and transit
`times. The drug progabide, which
`is unstable under acid
`conditions,
`is used
`to
`illustrate
`the delicate balance between physical
`and physiological
`variables and
`the use of physical models describing
`the biopharmaceutics
`and pharmaco-
`kinetic events
`for the design of an appropriate delivery system. Similarly,
`the use of in vitro
`dissolution
`tests and diffusion
`experiments
`can provide essential
`information
`on the mech-
`anisms of drug release but are not necessarily good predictors of the in viva situation. The
`non-invasive
`technique
`of gamma scintigraphy
`has been used
`to follow
`in vivo release rates
`and to relate
`these
`to pharmacokinetic
`parameters. The same scintigraphic method has been
`used
`to follom
`the gastrointestinal
`transit of a variety of controlled
`release systems
`to in-
`clude pellets, matrix systems and osmotic pumps. The effect of dosage characteristics
`and
`physiological
`variables, part~~u~ar~y diet, can be evaluated. Large (>5 mm) units will be
`retained
`in a fed stomach while smaller units can empty
`in a similar way
`to liquids. Small
`intestine
`transit
`time
`is short (3 h rt 1 h) for all systems studied. This result has implications
`for the design of controlled
`release delivery
`systems
`for drugs with poor absorption
`in the
`large intestine, as well as for the development
`of positioned
`release systems (colon
`targeting).
`
`INTRODUCTION
`
`Controlled release systems for oral use in-
`clude
`those designed
`simply
`to delay
`the
`release of a drug (for example an enteric
`coated system), as well as more complicated
`systems in the form of matrix tablets, coated
`pellets, osmotic pumps, etc., designed
`to
`release the drug over an extended period of
`time, either
`in a continuous manner
`(sus-
`
`*Paper presented at the Second International Sym-
`posium on Recent Advances
`in Drug Delivery Sys-
`tems, February 27, 28 and March 1, 1985, Salt Lake
`City, UT, U.S.A.
`
`tamed release) or as a series of pulses (timed
`release). Delivery
`systems,
`for positioned
`release at specific
`sites close
`to so-called
`‘“absorption windows” or for localized treat-
`ment can also be considered under the general
`title of controlled release systems.
`The rational design and evaluation of effec-
`tive controlled release delivery systems needs
`trinity of drug,
`to take
`into account
`the
`delivery
`and destination.
`Each one is inter-
`related to the other two and it is essential to
`consider all aspects and constraints
`for the
`successful development of a new system. Fac-
`tors such as the solubility and stability of the
`
`0168-3659/85/$03.30
`
`G 1985 Elsevier Science Publishers B.V.
`
`

`
`28
`
`regions
`the different
`from
`its absorption
`drug,
`release
`tract,
`the
`of
`the
`gastrointestinal
`characteristics
`of the delivery
`system
`in vitro
`and
`in uivo and gastrointestinal
`transit
`all
`need to be evaluated.
`Each of the
`three parts of the trinity will
`be considered
`in turn.
`In doing
`so it is as-
`sumed
`that
`the pharmacokinetics
`of the drug
`have been well characterised
`and a controlled
`release
`dosage
`form
`is required
`to
`fulfil
`a
`well defined
`clinical
`need,
`for example
`to
`change
`the dosage
`regimen,
`improve patient
`compliance,
`enhance
`the total bioavailabihty,
`reduce adverse
`reactions
`and side effects, etc.
`Hopefully,
`data
`on
`the
`relationship
`be-
`tween pharmacokinetic
`profile,
`the drug and
`(pharmacodynamic
`and
`clinical)
`response
`will be available
`to
`the pharmaceutical
`sci-
`entist. However,
`it is not unknown
`for con-
`trolled
`release
`systems
`to be requested
`and
`even developed, without
`reference
`to effec-
`tive blood
`(and
`tissue)
`levels and
`the
`ther-
`apeutic
`index
`of
`the drug, or
`the unavail-
`ability of same!
`
`-CHARACTERISTICS
`DRUG
`ENTITY
`
`Preformulation studies
`
`OF THE CHEMICAL
`
`of a
`characteristics
`The physicochemical
`are
`drug relevant
`to
`its biological
`availability
`determined
`at
`the preformulation
`stage of
`drug development.
`Data on such
`factors
`as
`PK a, pH,
`stability,
`solubility
`and partition
`(distribution)
`profiles,
`can be obtained
`by
`standard
`physicochemical
`methods.
`The rel-
`evance of some of these values
`to the biolog-
`ical situation
`has been questioned,
`particular-
`ly with
`regard
`to partition
`(distribution)
`data and its use in predicting drug absorption.
`The studies of Ho and others
`[l]
`on mem-
`brane permeability
`and
`the role of unstirred
`layers have shown
`conclusively
`that
`a large
`partition
`(distribution)
`coefficient
`) does
`(K,
`not necessarily
`lead to enhanced permeability,
`since at a limiting value of K,
`the process of
`
`as-
`one
`from
`changes
`control
`diffusional
`to one associated
`sociated with the membrane
`layers adjacent
`to
`with
`the aqueous unstirred
`the effect
`of
`the membrane.
`Consequently
`mucus
`layer
`in the gastrointestinal
`tract
`(and
`the glycocalyx)
`on drug
`transport
`is now
`receiving
`attention
`[Z] . Others
`[3]
`have
`questioned
`the use of 1-octanol
`as the solvent
`of choice
`in distribution
`experiments
`and
`have proposed
`that
`liposome
`systems may
`be more valid, although more difficult
`to use
`experimentally.
`to the
`relevant
`tests more
`Preformulation
`biological
`environment,
`such as those based
`on perfused
`intestinal
`loops
`in the
`(in situ)
`rat, can provide valuable
`insight
`into
`the ab-
`sorption
`behaviour
`of a compound
`in differ-
`ent regions of the gastrointestinal
`tract,
`and
`the
`existence
`of
`absorption
`windows
`or
`processes
`for
`facilitated
`transport
`[4]. As
`will be shown below,
`a significant
`and reli-
`able absorption
`of a compound
`from
`the large
`intestine
`may
`be a prerequisite
`for
`the
`successful development
`of a controlled
`release
`system
`intended
`for once daily administra-
`tion,
`particularly
`if
`the drug has a short
`half-life.
`The
`cannulation
`of
`thoracic
`(or
`mesenteric)
`lymph vessels can show whether
`the
`compound
`is transported
`lymphatically
`to any
`significant
`extent
`and whether
`this
`route,
`that has the advantage of avoiding
`first
`pass metabolism
`by the
`liver, has any benefit
`through
`the use of appropriate
`lipid contain-
`ing oral formulations
`or through
`the prodrug
`approach
`by making more
`lipophilic
`deriv-
`atives [5] .
`
`Physical models
`
`on
`information
`and
`data
`Preformulation
`to be correlated
`need
`physiological
`function
`approach
`to
`the
`so as to provide
`a rational
`choice
`of a delivery
`system. The new anti-
`convulsant
`progabide
`is an interesting
`exam-
`ple of the need to consider physiology
`as well
`as physical
`chemistry.
`Preformulation
`infor-
`mation
`for progabide
`is provided
`in Table 1
`(61. The drug
`is a weak base with a pK, of
`
`

`
`29
`
`TABLE
`
`2
`
`- Bioavailability
`Progabide
`dose = 600 mg)
`
`(mean + s.e.m.
`
`(n = 6);
`
`Formulation
`
`Drug size
`
`AUC (mg ml-’ h)
`
`Capsule
`Capsule
`Tablet
`Gaotroresistant
`tablet
`
`micronized
`coarse
`micronized
`
`9836
`4508
`8607
`
`f 2950
`* 655
`f: 819
`
`micronized
`
`4590
`
`* 1393
`
`the delivery
`in the stomach,
`from degradation
`powder
`into the intestines,
`of the undissolved
`it has minimal
`solubility,
`to
`a pH where
`disadvantageous.
`was even more
`An alter-
`native
`strategy was
`considered
`that
`took
`into account
`the high solubility
`of the drug
`at
`the acid pH of
`the
`resting
`stomach
`and
`the
`rapid emptying
`of the resultant
`solution
`of the drug from
`the stomach
`(tlh < 1 h) that
`could minimize
`losses due
`to degradation.
`The bioavailability
`of
`the drug
`in the un-
`protected
`form was
`indeed better
`than
`for
`the enteric coated system
`(Table 2).
`This
`compromise
`between
`necessary
`solubility
`and stability
`considerations
`and the
`importance
`of physiological
`factors, has been
`incorporated
`into a physical model
`[7]
`(Fig.
`1)
`that
`takes
`into
`account
`not
`only
`the
`factors discussed above, but other
`issues such
`as the precipitation
`of a proportion
`of the
`dissolved drug as it enters
`the intestines
`and
`the
`redissolution
`the
`fine particles
`so
`of
`created. Measured or estimated
`values of the
`various
`rate constants
`can be used
`to derive
`blood
`level-time
`profiles
`not only
`for pro-
`gabide but also for other drugs with similar
`stability
`problems
`and
`to assess the changes
`that would
`occur
`if
`formulation,
`dosage
`or
`physiological
`parameters
`were
`altered.
`The model has been validated
`in the rabbit
`by following
`the effects on the bioavailability
`of change
`in the particle
`size of administered
`progabide
`as well as the suppression
`of acid
`in the stomach by the use of an HZ-antagonist
`[6]. Both
`experiments
`indicated
`the over-
`riding
`importance
`of the dissolution
`step for
`
`(l-(4-chlorophenyl)1-(3-fluoro-6-
`-
`Progabide
`hydroxyphenyl))4-methylenimino
`butyramide
`General
`formula:
`C,,H,,ClFN,O,.
`Molecular weight:
`334.18.
`
`TABLE
`
`I
`
`Progabide
`
`- Preformulation
`
`profile
`
`(data at 37°C)
`
`PK,
`coefficient
`Distribution
`(octanol/water)
`
`(free base)
`
`3.41
`
`933
`
`in aqueous
`Stability
`(rrh) (min)
`
`solution
`
`Solubility
`(mg/l)
`
`in aqueous buffers
`
`18 (pH = 2.2)
`130
`(pH = 6.3)
`
`(pH = 2.2)
`9093
`44 (pH = 6.3)
`
`rate constant
`Absorption
`(rat gut loop, pH 6)
`(salicylic
`acid)
`
`(k, mm’)
`
`0.0854
`0.101
`
`at pH
`soluble
`3.41 at 37°C. It is reasonably
`soluble
`values below 3.0 but
`is very poorly
`above pH 4.0. The compound
`is hydrolysed
`to
`release GABA and a benzophenone.
`The
`pH-hydrolysis
`profile
`is in
`the
`form of a
`stability
`curve, maximum
`being
`bell-shaped
`found
`at around pH 6.3. At pH 2.2 the half-
`life of the compound
`at 37°C is about 18 min.
`The octanol-water
`distribution
`coefficient
`of
`the compound
`is in the region of 103. In situ
`intestinal
`loop
`studies have shown
`that
`the
`compound
`is rapidly
`absorbed
`in the small
`( tl12 = 8.1 min,
`cf. salicylic
`acid,
`intestine
`tlh = 6.9 min).
`In view of the poor stability
`of the compound
`at gastric pH a controlled
`release
`system was developed
`in the form of
`an enteric
`coated
`soft gelatin
`capsule
`that
`contained
`the drug
`as micronized
`powder
`(300 mg dose)
`dispersed
`in vegetable
`oil.
`However,
`bioavailability
`studies conducted
`in
`man (Table 2) revealed
`low levels of the drug
`and
`its metabolites
`in the blood
`following
`oral administration.
`Thus, while
`the enteric
`coat had been effective
`in protecting
`the drug
`
`

`
`30
`
`oral
`
`administratlon
`
`,
`
`‘1
`
`gastric
`py
`ydat ion
`
`je/
`
`2
`
`gastric
`
`absorption
`
`(kg)
`
`>
`
`ITI
`
`.
`
`I
`
`intestinal
`absorption
`
`(k,)
`
`elimination
`
`(kg)
`
`I
`
`Fig.
`1. Pharmacokinetic/biopharmaceutical
`- drug in eolution;
`shaded boxes
`
`- drug
`
`for drug absorption
`model
`in suspenrion.)
`
`following
`
`oral administration.
`
`(Open boxef
`
`the
`increasing
`instance
`for
`the compound,
`stomach
`pH by
`an H,-antagonist
`gave a
`marked
`reduction
`in bioavailability
`contrary
`to what would
`be predicted
`from
`stability
`considerations
`alone (Fig. 2).
`Ho, Higuchi and others
`[8] have developed
`a similar
`type of model
`approach,
`but have
`restricted
`this to the small intestine. Here the
`inter-relationships
`between
`particle
`dissolu-
`tion, drug permeability
`and
`intestinal
`transit
`have been
`considered.
`A unifying
`concept
`of the “reserve
`length” was introduced,
`this
`being
`the
`length of absorptive
`surface
`(small
`intestine)
`available
`after
`the drug had been
`absorbed.
`Thus,
`a drug
`that
`is rapidly
`and
`effectively
`absorbed
`in
`the
`small
`intestine
`would have a large reserve
`length. An equa-
`tion was presented whereby
`it is possible
`to
`determine
`the required
`particle
`size of a drug
`suspension,
`so that
`it would dissolve
`and be
`absorbed within
`the absorptive
`length of the
`small
`intestine
`(about
`300 cm). A similar
`approach was proposed
`for the calculation
`of
`the
`release
`characteristics
`of a controlled
`release
`pellet
`system
`so
`that
`too would
`it
`deliver
`its drug
`load uniformly
`within
`the
`length
`of
`the
`small
`intestine.
`The various
`physiological
`factors,
`namely
`flow
`rates
`in
`
`I.V.
`i2Omg/kg)
`
`0631.l~
`suspensial
`(n&l
`
`q Progabide
`0 Benzophen
`@ Metagabrde
`
`and metabolites
`of progabide
`2. BioavaiIability
`Fig.
`A:
`(ZOO mg/kg).
`administration
`rabbit
`-
`oral
`in
`(20 mgikg)
`(n = 5); B: micronized
`(n = 4); C:
`i.v.
`40-63
`urn suspension
`(n = 5); D: 212-300
`pm sus-
`pension
`(n = 3); E: 40-63
`pm
`suspension
`+ i.v.
`ranitidine
`(10 mg/kg)
`(n = 3).
`
`

`
`segments of the small intestine,
`the different
`the spreading of a particulate
`system during
`transit
`and
`transit
`times
`for passage
`from
`duodenum
`to
`ileocaecal
`valve, were
`taken
`from
`the limited
`information
`available
`in the
`literature
`on
`foodstuffs.
`The
`transit
`and
`spreading behaviour
`of pharmaceutical
`dosage
`forms
`is discussed
`further below.
`
`- CHARACTERISTICS
`DELIVERY
`DOSAGE FORM
`
`OF THE
`
`for the con-
`The range of systems available
`trolled
`delivery
`of drugs
`to
`the gastrointes-
`tinal
`tract
`is huge, and it is not
`the
`intention
`to review
`these here. Instead
`it will be stressed
`that
`the nature
`of
`the delivery
`system will
`be dictated
`by the properties
`and dose of the
`drug,
`the purpose
`for controlling
`the release
`of the drug and the interaction
`of constraining
`physiological
`and pathological
`factors.
`For
`example,
`as will be discussed
`further
`below,
`there
`is little point
`in attempting
`to develop
`a once daily, multip~ticulate
`system
`for a
`compound
`that
`is not absorbed
`from
`the large
`intestine,
`or has an absorption
`window
`in
`the duodenum
`or jejunum.
`
`Hydroxypropylmethylcelluiose
`
`(HPMCI
`
`investigating
`In recent years we have been
`the
`use
`of
`hydroxypropylmethylcellulose
`(and
`its modifications
`in the
`form of Syn-
`chron)
`for use as a controlled
`release system
`[9]. A variety
`of polymers
`of different
`molecular
`weight
`is available. As a means
`for making
`controlled
`release
`formulations
`the system has the advantage
`of needing no
`special machinery
`and
`is extremely
`robust.
`Wide
`tolerancies
`can be permitted
`in produc-
`tion
`factors
`such
`as compaction
`pressure.
`The
`release
`profile
`of a drug
`incorporated
`into
`the matrix
`can be altered by change
`in
`the polymer
`content
`as well as its molecular
`weight,
`the addition
`of soluble or insoluble
`excipients,
`surface
`active
`agents,
`etc.
`[lo].
`
`31
`
`the well
`to
`conform
`systems
`simple
`While
`(linear plot of
`release profile
`known matrix
`root of time),
`quantity
`released versus square
`zero-order
`release
`can be achieved
`by
`the
`addition
`of complexing
`agents
`that not only
`alter
`the solubility
`of the drug but also the
`viscosity
`of the hydrated
`polymer
`[lo]
`(Fig.
`3). Reasonable quantities of polymer
`(> 10%)
`may be required
`for an effective
`controlled
`release
`system based upon a dry direct com-
`pression matrix
`system, while much
`smaller
`quantities
`are necessary
`if a granulation
`step
`is included
`in
`the production
`process. The
`actual process
`of release of a drug
`from an
`HPMC matrix
`is a complex
`one
`involving
`water
`penetration
`into
`the
`drug matrix;
`hydration
`and gelation
`of the polymer,
`dif-
`fusion of the dissolved drug
`in the resultant
`gel and erosion
`of
`the gel
`layer
`[II].
`The
`modelling
`of these processes
`is further
`com-
`plicated
`by the swelling of the system
`[ 12 J .
`A conventional
`dissolution
`test will provide
`the
`resultant
`of
`these many
`separate
`pro-
`cesses, different
`ones being
`the
`rate control-
`ling at various
`stages of the release process.
`Recently we have examined
`the diffusional
`properties
`of HPMC systems by means of a
`novel ultrasound method
`[13 3. The penetra-
`tion of water
`into
`the drug matrix was ex-
`tremely
`slow and was affected
`by the pres-
`ence of dissolved
`solutes. The diffusion
`of
`water
`in a hydrated
`gel system was also quite
`slow (> 1 X loo6 cm2 s-‘) but solutes dis-
`
`it m e
`
`of chlorpheniramine
`release
`Fig. 3. The
`tablets. Legend:
`Methocel
`El5 matrix
`0, 15% sodium dodecyl
`sulphate.
`
`from
`(5%)
`0, no additive;
`
`

`
`32
`
`in the gel or in the diffusion medium
`solved
`increased
`the
`rate of diffusion
`(1 X
`greatly
`lo-’
`cm2 s-l). These
`results have been
`inter-
`preted
`in terms of the nature of bound water
`in HPMC gels and the effect of added solutes
`in reducing
`such binding
`[13].
`Interestingly,
`the
`release
`of a model
`drug
`from
`a drug
`matrix
`system made
`just
`from polymer
`and
`drug
`is more
`rapid
`than
`that provided
`by a
`40% hydrogel
`of HPMC (Fig. 4). This demon-
`strates
`the considerable
`difference
`between
`equilibrium
`and non-equilibrium
`states. These
`HPMC hydrogels
`have an interesting
`rubber-
`like consistency which may have applications,
`not only
`for oral use, but also
`for buccal,
`and
`subcutaneous
`routes.
`rectal,
`vaginal
`The
`low water activity
`in such systems should
`allow
`the
`incorporation
`of drug with formula-
`tion
`limitations
`imposed
`by poor
`stability.
`
`from
`
`(5%)
`of chlorpheniramine
`release
`Fig. 4. The
`tablets
`and 4% hydrogel.
`Methocei K4M matrix
`Matrix systems based on HPMC are normal-
`ly administered
`in the form of single units.
`Recently we have developed multiparticulate
`pellet
`(minimatrix)
`systems
`that can be for-
`mulated
`to give equivalent
`release
`profiles
`to
`the
`single unit
`system with
`its much
`smaller
`surface
`area. The
`gastrointestinal
`transit behaviour
`of single and multiple
`unit
`systems
`is discussed below.
`
`In vim evaluation of drug release
`it
`test, whether
`The
`in vitro dissolution
`be USP-Paddle,
`basket apparatus or variations
`
`rotating
`system,
`through
`flow
`as a
`such
`following
`are useful means
`etc,
`bottles
`for
`release profiles
`and the effect of formulation
`procedures.
`However,
`they may not be
`in-
`dicative
`of the situation
`in uivo where agita-
`tion
`and pH conditions
`can differ widely
`within
`the gastrointestinal
`tract.
`For
`this
`reason we have explored methods
`for provid-
`ing data on release profiles
`in uiuo [ 141. The
`deconvolution
`of pharmacokinetic
`data can
`be used
`in this way but
`it requires
`a large
`number
`of blood
`samples
`and
`therefore
`it
`is not
`suitable
`for
`the development
`of drug
`delivery
`systems.
`Instead, we have used ex-
`tensively
`the
`non-invasive
`technique
`of
`gamma scintigraphy.
`This technique
`not only
`provides
`data on release
`characteristics,
`but
`also on
`the position
`of the delivery
`system
`within
`the gastrointestinal
`tract.
`is labelled
`The
`formulation
`under
`study
`emitting
`with
`solute
`containing
`a gamma
`tlj2 = 6 h;
`radionuclide
`(e.g., technetium-99m,
`indium-111,
`a model
`ty2 = 2.7 h). Normally
`non-absorbed
`solute
`such
`as diethylenetri-
`aminepentaacetic
`acid (DTPA) or the imino-
`diacetic
`acid analogue
`of
`lidocaine
`(HIDA)
`is used
`to mimic
`a drug molecule
`being
`released
`by a process
`of diffusion, while a
`fine particle
`size
`ion-exchange
`resin
`is used
`to provide
`information
`about
`the
`integrity
`of a delayed
`release
`(e.g., enteric
`coated)
`tablet
`or
`the
`erosion
`of a matrix
`system.
`(The
`labelling
`of an actual
`drug molecule
`with
`a native
`gamma
`emitting
`isotope
`is
`possible,
`since
`the suitable
`isotopes
`of
`but
`carbon,
`oxygen
`and nitrogen
`are
`so short
`lived,
`special
`and
`expensive
`facilities
`are
`required.)
`In diffusion
`release
`studies,
`ex-
`tensive
`evaluations
`under
`different
`condi-
`tions of pH, agitation,
`etc., are carried out
`to ensure
`that
`the
`release
`of
`the
`in vitro
`marker molecule mirrors
`that of
`the drug
`under
`investigation.
`(If desired,
`the
`molecule
`actual drug of
`interest
`can be added
`to
`the
`formulation
`and
`its appearance
`in the blood
`or urine
`followed
`using conventional
`meth-
`ods.)
`In such cases
`the
`scintigraphic
`tech-
`nique
`serves as an adjunct
`to
`the pharmaco-
`
`

`
`informa-
`by providing
`investigation
`kinetic
`tion
`about
`the position
`of
`the
`formulation
`in
`the gastrointestinal
`tract
`and
`its
`in uiuo
`release characteristics.
`The amount
`of radio-
`labelled material
`incorporated
`into
`the
`for-
`mulation
`is as small as a few milligrammes
`and therefore
`the labelling procedure
`does not
`alter
`the physical
`properties
`of the delivery
`system.
`After
`the
`labelled
`formulation
`is dosed,
`the volunteer
`is placed
`in front of a conven-
`tional
`gamma
`camera
`(40 cm field of view)
`and by using external
`and internal non-inter-
`fering markers,
`the position
`of the delivery
`system
`in
`the gastrointestinal
`tract
`can be
`ascertained.
`The associated
`computer
`system
`is then used
`to create
`a “region of interest”
`around
`the
`image of the delivery
`system and
`the quantity
`of radioactivity
`remaining
`there-
`in can be determined.
`In this way an in uiuo
`release
`profile
`is created
`that
`can be com-
`pared with
`that
`found
`in uitro (Fig. 5) [9].
`Modern
`gamma
`cameras
`have
`the capability
`of measuring
`two
`radionuclides
`of differing
`energy
`characteristics
`simultaneously,
`and
`therefore
`it is a simple matter
`to administer
`to
`the
`same subject
`two
`formulations
`with
`different
`release characteristics,
`thereby
`con-
`ducting
`a cross-over
`study
`on
`the one oc-
`casion!
`The gamma
`camera
`technique
`has
`been used
`to evaluate
`not only
`the HPMC
`100
`
`\6
`
`lfl.5)
`,n ntro
`.
`0 !” viva L” ILLI
`
`10
`
`2 . 0
`
`(Time)i
`
`IhG)
`
`30
`
`Fig. 5. In vitro-in uiuo correlation.
`Release of 99mTc-
`f a.e.m.). Legend:
`EHIDA
`from matrix
`tablets
`(mean
`0, in vitro (n = 5); o, in uiuo (n = 6 (<2 b), 4 (> 2 h)).
`
`33
`
`type of system, but also the osmotic pump
`system
`for controlled
`release
`[15]. This was
`found
`to have an in uiuo release profile
`iden-
`tical
`to that found
`in vitro. Furthermore,
`the
`osmotic
`pump
`(Osmet) has considerable
`ad-
`vantage
`in preliminary
`investigations
`on drug
`absorption
`and
`controlled
`release
`systems.
`The Osmet device can be filled with a solution
`or suspension
`of drug under evaluation
`and
`provides
`a well characterised
`and constant
`(zero-order)
`release profile. The position
`of
`the device
`in the gastrointestinal
`tract can be
`ascertained
`by
`adding
`a small amount
`of
`labelled material
`and
`then
`passage of
`the
`system
`through
`the
`gastrointestinal
`tract
`can be correlated with changes
`in the pharma-
`cokinetic
`profile
`of
`the drug.
`In
`this way,
`absorption windows,
`lack of or erratic absorp-
`tion
`at certain
`sites
`(e.g.,
`colon)
`can be
`evaluated.
`Pumps with
`long start up
`times
`(e.g., 4 h) can be delivered
`to
`the
`lower
`in-
`testines
`the release of the
`filled drug
`before
`(and marker) commences.
`A further
`obvious
`use of the scintigraphic
`technique
`is
`the
`evaluation
`of controlled
`release
`systems
`in the form of enteric coated
`tablets. Delayed
`(positioned)
`release
`further
`down
`the gastrointestinal
`tract
`can be fol-
`lowed
`in exactly
`the same way as discussed
`below.
`The
`foregoing
`describing
`the use of scinti-
`graphic methods
`for
`the evaluation
`of drug
`release
`can be applied well
`to a single unit
`system, but not
`to a multiparticulate
`system
`such as controlled
`release pellets. For, while
`it is possible
`to determine
`the position
`and
`quantity
`of the dose
`in a given region of the
`gastrointestinal
`tract
`[ 161,
`the scintigraphic
`method
`is not
`able
`to distinguish whether
`the activity
`is still within
`the pellet or has
`been released and is in close proximity. How-
`ever,
`the combination
`of gamma scintigraphy
`with
`the
`related
`technique
`of perturbed
`angular
`correlation
`does
`permit
`both
`the
`position
`and
`the
`release
`to be evaluated
`simultaneously.
`Radionuclides
`that decay by
`emitting
`two gamma
`rays
`in cascade,
`such as
`indium-111,
`emit
`the
`rays with
`a certain
`
`

`
`34
`
`between
`correlation
`This
`them.
`angular
`correlation
`can be perturbed
`if the physical
`environment
`of
`the
`nucleus
`changes,
`for
`example
`from
`the solid
`to
`the
`liquid
`state.
`Beihn and Digenis
`[17] have used this meth-
`od
`to follow
`the dissolution
`rate of indium-
`111 chloride
`from a lactose
`tablet
`in a human
`subject.
`
`- CHARACTERISTICS
`DESTINATION
`GASTROINTESTINAL
`TRACT
`
`OF THE
`
`Physiology
`
`gastrointestinal
`the
`of
`physiology
`The
`in which
`tract
`and
`the manner
`this can be
`affected
`by disease
`conditions
`and adminis-
`tered drugs has a direct bearing on the design
`of controlled
`release
`systems. The generally
`accepted
`value
`for
`the pH of
`the
`resting
`stomach
`is about
`2.0, but values as high as
`6.0 have been recorded
`in normal
`individuals
`by aspiration
`or the use of radiotransmitting
`(Heidelberg)
`capsules
`[18]. The presence
`of
`food will raise
`the pH
`to 5 or 6, as will ad-
`ministered
`antacids
`and HZ-antagonists.
`The
`elderly
`have
`less acidic
`stomach
`contents
`than the young.
`The process of gastric emptying
`is affected
`by
`the quantity
`and nature
`of food
`in the
`stomach
`as well as the size and the digestibil-
`ity of the administered material
`[ 191. Solu-
`tions are emptied
`rapidly
`from
`the stomach,
`as are small particles
`of
`less than
`l-2 mm
`in diameter
`[20]. Particles greater
`than
`this
`have
`to be
`reduced
`in size by
`the normal
`digestive
`process,
`or
`if nondigestible,
`to
`await
`the end of the digestive phase and
`to
`be cleared
`from
`the stomach by the so-called
`interdigestive
`housekeeper
`wave
`[21] . This
`means
`that
`a single unit dosage
`form,
`ad-
`ministered
`to a fed stomach, will remain
`at
`that site until
`the end of the digestive phase.
`In contrast,
`a solution
`formulation
`(and
`dissolved drug), as well as small pellets, will
`be emptied
`during
`the digestive phase. Deliv-
`ery systems, administered
`to a fasted stomach,
`
`the stomach and can
`from
`rapidly
`will empty
`the small intestine
`to
`be transported
`through
`the
`terminal
`ileum
`in as little as 1.5-2
`h by
`an
`interdigestive
`housekeeper
`wave
`[22].
`Thus,
`if the
`important
`absorption
`sites
`for
`the administered
`drug are in the upper small
`intestine,
`the measured
`bioavailability
`in the
`fasted
`state will be considerably
`different
`to that measured
`in the fed state.
`Certain disease conditions
`such as inflam-
`matory
`lesions or disorders
`of gut motility
`as well as administered
`drug can affect
`transit
`behaviour
`[23]. Similarly,
`for patients with
`partial
`obstruction
`or narrowed
`lumen,
`the
`passage of a single unit
`formulation may be
`impeded
`[24].
`
`Gastrointestinal transit
`
`three years, we have fol-
`last
`the
`During
`lowed
`the gastrointestinal
`transit of a variety
`of pharmaceutical
`formulations
`(solutions,
`pellets, matrix
`tablets,
`osmotic
`pumps,
`etc.)
`using
`the
`technique
`of gamma
`scintigraphy
`[9, 14-161.
`To date, studies have been con-
`ducted
`in over 150 subjects. The majority
`of these people have been young male healthy
`volunteers,
`but
`some
`limited
`investigations
`have been carried
`out
`in elderly women,
`as
`well as in ileostomy
`subjects.
`Some data
`from
`one of our studies
`are
`shown
`in Fig. 6 for
`the
`transit
`of a pellet
`formulation
`(size 0.3-1.2 mm)
`in different
`regions of the gastrointestinal
`tract,
`together
`with
`representative
`scintiscans.
`The
`transit
`behaviour
`of
`solution,
`pellet
`and osmotic
`pumps
`[25]
`are summarised
`in Fig. 7, and
`compared
`to
`recently
`published
`data
`on
`solutions
`and solids
`in the form of foodstuffs
`[26].
`From
`these data and other
`associated
`studies
`the
`following major conclusions
`can
`be drawn:
`(i) Solutions
`and pellet
`systems
`empty
`quite
`rapidly
`from
`the stomach and the
`gastric
`emptying
`of pellet
`systems
`is
`delayed by the presence of food.
`(ii) Single unit systems
`can be retained
`in
`the stomach
`for long periods
`(10 h and
`
`

`
`35
`
`transit of pellets
`Fig. 6(a). Gastrointestinal
`diameter).
`Legend:
`l , stomach
`(St); 0, small
`
`ion exchange
`(““’ Tc-labelled
`i s.e.m.)
`(n = 6, mean
`intestine
`(SI); ~1, colon
`(total all regions).
`
`resin 0.9-l
`
`.2 mm
`
`Gastric emptying
`
`Small intestine
`
`transit
`
`Solutton Pellets
`
`Osmotic
`pumps
`
`Solution Pellets
`
`Osmotic
`pumps
`
`12 -
`
`lo-
`
`1 tllN
`
`15tllN
`
`3Q H I N
`
`1.5 HOUR
`
`4.5 HOUR
`
`QHOUR
`
`I_
`
`forms.
`of dosage
`transit
`7. Gastrointestinal
`Fig.
`Legend: LB .-- light breakfast
`(1500 kJ); HB - heavy
`breakfast
`(3600
`kJ); FA
`-
`fasted;
`SM
`standard
`meal.
`(a) Data
`from Ref.
`[ 261,
`solution
`and solid
`I- 5 mm
`in length).
`( fibre
`
`(iii)
`
`(iv)
`(v)
`
`*
`27 HOUR
`
`showing
`
`gastro-
`
`if administered
`
`after
`
`a heavy
`
`longer)
`meal.
`is remarkably
`transit
`intestine
`Small
`independent
`constant
`and
`of
`the
`nature of the dosage
`form or the nutri-
`tional state of the subject.
`The average small intestine
`transit
`time
`is of the order of 3 h + 1 h.
`Single
`units
`can be held
`for
`long
`periods
`(4-12
`h) at the ileocaecal valve
`before being moved
`into the colon.
`
`IQHOUR
`
`Fig. 6(b). Representative
`intestinal
`transit of pellets.
`
`22 HOUR
`
`1
`scintiscans
`
`

`
`36
`
`old
`for healthy
`pattern
`transit
`(vi) The
`for
`subjects
`is no different
`to
`that
`healthy young subjects.
`(vii) Total
`transit
`in young
`healthy males
`can be as short
`as 6-8
`h, especially
`for those on a vegetarian diet.
`is
`(viii) The
`transit
`of
`delivery
`systems
`similar
`to
`that of
`foods
`in that
`the
`intestine
`stomach
`and not
`the
`small
`discriminates
`between
`liquids and solids.
`(ix) Following
`rapid gastric emptying
`there
`is little dispersion
`(spreading)
`of liquid
`or pellet systems
`in the small intestine.
`These
`results have definite
`implications
`for
`controlled
`release
`systems.
`For
`instance,
`a
`number
`of recently
`developed
`controlled
`or
`sustained
`release
`products
`have claims
`for
`zero-order
`release
`over
`12 or even
`24 h
`periods
`of time. The relevance
`of such data
`to the clinical situation must be questioned
`if
`the drug
`is poorly
`or erratically
`absorbed
`from
`the
`large intestine
`or can undergo
`trans-
`formation
`by colonic
`bacteria. Dosage on an
`empty
`stomach,
`or after a light meal, could
`result
`in the delivery
`system
`arriving at the
`colon
`after
`only
`3 h. Consequently
`the
`greater proportion
`of the drug will be deliver-
`ed
`to
`a non-optimal
`site. Thus, data
`for
`regulatory
`submissions,
`showing
`the equiv-
`alence of a single unit controlled
`release sys-
`tem,
`to multiple
`doses of the drug over
`the
`same
`time
`scale,
`should
`be conducted
`in
`fasted
`and
`non-fasted
`subjects
`using
`in-
`dividuals with
`long and
`short
`total
`transit
`times.
`if
`to be gained
`is a clear advantage
`There
`a single unit
`system
`can be retained
`in the
`stomach
`for
`a significant
`period
`of
`time.
`The drug released
`from
`the system will empty
`from
`the
`stomach
`and have
`the whole of
`the small
`intestine
`available
`for absorption.
`For
`this
`reason attention
`has been
`focussed
`on
`floating
`devices
`[27]
`and
`the use of
`“mucoadhesives”
`to delay gastric
`emptying
`[28]. However,
`the clinical data
`in support
`of such approaches
`are few and success has
`been
`limited
`except
`in the
`field of animal
`medicine
`where
`gastric
`emptying
`can
`be
`
`prevented
`the delivery
`
`by the size and/or
`system.
`
`the density
`
`of
`
`Positioned release of drugs in the colon
`
`of
`transit
`the
`of
`constancy
`relative
`The
`can
`intestine
`in
`the small
`systems
`delivery
`that
`the design of systems
`be exploited
`for
`will provide positioned
`release.
`In certain
`disease
`co