Journal of Controlled Release, 2 (1985) 27-38
`Elsevier Science Publishers BY., 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 Nottingham, University Park, Nottingham NG7 2RD (Great Britain)
`
`The design and evaluation of delivery systems for the gastrointestinal tract requires knowl-
`edge about three inter-related topics, the drug, the delivery system and the destination
`intended, Preformulation data describing the physicochemical characteristics of a drug
`molecule need to be considered in relation to known physiological variables such as gastro-
`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 vivo 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 follow 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, particularly 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 ± 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
`to take into account the trinity of drug,
`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 © 1985 Elsevier Science Publishers B.V.
`
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`28
`
`drug, its absorption from the different regions
`of the gastrointestinal tract, the release
`characteristics of the delivery system in vitro
`and in vivo 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 bioavailability,
`reduce adverse reactions and side effects, etc.
`Hopefully, data on the relationship be-
`tween pharmacokinetic profile, the drug and
`response (pharmacodynamic and clinical)
`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!
`
`DRUG — CHARACTERISTICS OF THE CHEMICAL
`ENTITY
`
`Preformulation studies
`
`The physicochemical characteristics of a
`drug relevant to its biological availability are
`determined at the preformulation stage of
`drug development. Data on such factors as
`pKa , 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 [1] on mem-
`brane permeability and the role of unstirred
`layers have shown conclusively that a large
`partition (distribution) coefficient (KD ) does
`not necessarily lead to enhanced permeability,
`since at a limiting value of KD the process of
`
`diffusional control changes from one as-
`sociated with the membrane to one associated
`with the aqueous unstirred layers adjacent to
`the membrane. Consequently the effect of
`mucus layer in the gastrointestinal tract (and
`the glycocalyx) on drug transport is now
`receiving attention [2] . 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.
`Preformulation tests more relevant to the
`biological environment, such as those based
`on perfused (in situ) intestinal loops in the
`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
`
`Preformulation data and information on
`physiological function need to be correlated
`so as to provide a rational approach to the
`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
`[6] . The drug is a weak base with a pKa of
`
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`

`CI
`( 1 -(4 -chloropheny1)-1-( 3-fluoro-6-
`Progabide (cid:9)
`hydroxypheny1))4-methylenimino butyramide
`General formula: C,,H,,C1F1\12 02 . Molecular weight:
`334.78.
`
`TABLE 1
`
`Progabide — Preformulation profile (data at 37°C)
`
`pKa
`Distribution coefficient (free base)
`(octanol/water)
`Stability in aqueous solution
`(t1/2 ) (min)
`Solubility in aqueous buffers
`(mg/1 )
`Absorption rate constant (k, min ')
`(rat gut loop, pH 6)
`(salicylic acid)
`
`3.41
`
`933
`18 (pH = 2.2)
`130 (pH = 6.3)
`
`9093 (pH = 2.2)
`44 (pH = 6.3)
`
`0.0854
`0.101
`
`3.41 at 37°C. It is reasonably soluble at pH
`values below 3.0 but is very poorly soluble
`above pH 4.0. The compound is hydrolysed
`to release GABA and a benzophenone. The
`pH—hydrolysis profile is in the form of a
`bell-shaped curve, maximum stability being
`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
`intestine (LA = 8.1 min, cf. salicylic acid,
`t1/2 = 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
`
`29
`
`TABLE 2
`
`Progabide — Bioavailability (mean ± s.e.m. (n = 6);
`dose = 600 mg)
`
`Formulation (cid:9)
`Capsule (cid:9)
`Capsule (cid:9)
`Tablet (cid:9)
`Gastroresistant
`tablet (cid:9)
`
`Drug size
`
`AUC (mg (cid:9)
`
`h)
`
`micronized 9836 ± 2950
`coarse
`4508 ± 655
`micronized 8607 ± 819
`
`micronized 4590 ± 1393
`
`from degradation in the stomach, the delivery
`of the undissolved powder into the intestines,
`to a pH where it has minimal solubility,
`was even more disadvantageous. 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 (ti, < 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 necessary compromise between
`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 of the fine particles so
`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 H2 -antagonist
`[6] . Both experiments indicated the over-
`riding importance of the dissolution step for
`
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`

`30
`
`oral administration
`
`f
`gastric
`dissolutio
`
`k1 )
`
`gastric
`degradation
`
`(k 2 )
`
`gastric
`empyting (cid:9)
`
`(k3)
`
`E
`
`intestinal
`,degradation
`(k4 )
`
`V
`
`C
`
`gastric absorption (k6)
`
`intestinal
`absorption (k 7 )
`
`elimination (k8 )
`
`intestinal
`dissolution
`(k5 )
`
`precipitation
`
`Fig. 1. Pharmacokinetic/biopharmaceutical model for drug absorption following oral administration. (Open boxes
`— drug in solution; shaded boxes — drug in suspension.)
`
`the compound, for instance increasing the
`stomach pH by an H2 -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 it too would
`deliver its drug load uniformly within the
`length of the small intestine. The various
`physiological factors, namely flow rates in
`
`40-63prn
`suspension
`(n.51
`
`I.V.
`(20mg/kg)
`(n.5)
`
`Micronized
`(n.4
`
`Progabide
`
`Benzophen
`Metagabicte
`
`212 -300pm
`suspension
`(n=3)
`
`40-63um
`suspension+
`I.V. Ranitidine
`(10 mg/kg)
`(n=3)
`
`Fig. 2. Bioavailability of progabide and metabolites
`in rabbit — oral administration (200 mg/kg). A:
`i.v. (20 mg/kg) (n = 5); B: micronized (n = 4); C:
`40-63 pm suspension (n = 5); D: 212-300 pm sus-
`pension (n = 3); E: 40-63 pm suspension + i.v.
`ranitidine (10 mg/kg) (n = 3).
`
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`the different segments of the small intestine,
`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.
`
`DELIVERY — CHARACTERISTICS OF THE
`DOSAGE FORM
`
`The range of systems available for the con-
`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, multiparticulate system for a
`compound that is not absorbed from the large
`intestine, or has an absorption window in
`the duodenum or jejunum.
`
`Hydroxypropylmethylcellulose (HPMC)
`
`In recent years we have been investigating
`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. [10] .
`
`31
`
`While simple systems conform to the well
`known matrix release profile (linear plot of
`quantity released versus square root of time),
`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 [10] (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 [11] . The
`modelling of these processes is further com-
`plicated by the swelling of the system [12] .
`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] . 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 10-6 cm2 s- ') but solutes dis-
`100
`
`1j 80
`
`60
`
`6:
`
`10
`
`20
`
`4
`
`5
`
`itme (1,1
`
`Fig. 3. The release of chlorpheniramine (5%) from
`Methocel E15 matrix tablets. Legend: o, no additive;
`• , 15% sodium dodecyl sulphate.
`
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`

`32
`
`solved in the gel or in the diffusion medium
`greatly increased the rate of diffusion (1 X
`10-5 cm2 s'). 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 113]. 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,
`rectal, vaginal and subcutaneous routes.
`The low water activity in such systems should
`allow the incorporation of drug with formula-
`tion limitations imposed by poor stability.
`
`100
`
`80
`
`60'-
`
`co
`
`20
`
`0
`
`Matrix
`ti
`
`Gel ti
`
`2 (cid:9)
`
`3
`
`4
`Time Ihr)
`
`5
`
`Fig. 4. The release of chlorpheniramine (5%) from
`Methocel K4M matrix tablets and 4% hydrogel.
`
`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 pipe evaluation of drug release
`
`The in vitro dissolution test, whether it
`be USP-Paddle, basket apparatus or variations
`
`such as a flow through system, rotating
`bottles etc, are useful means for following
`release profiles and the effect of formulation
`procedures. However, they may not be in-
`dicative of the situation in vivo 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 vivo [14] . 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.
`The formulation under study is labelled
`with solute containing a gamma emitting
`radionuclide (e.g., technetium-99m, t1/2 = 6 h;
`indium-111, t1/2 = 2.7 h). Normally a model
`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, but since the suitable isotopes of
`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
`in vitro to ensure that the release of the
`marker molecule mirrors that of the drug
`molecule under investigation. (If desired, the
`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-
`
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`

`kinetic investigation by providing informa-
`tion about the position of the formulation
`in the gastrointestinal tract and its in vivo
`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 vivo
`release profile is created that can be com-
`pared with that found in vitro (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
`
`• in vitro (nr5)
`o in vivo (n=6,4)
`
`100
`
`80
`
`g 60
`
`E
`
`....L. 40
`
`20
`
`10
`
`20
`
`30
`
`(Time)t,
`
`Fig. 5. In vitro—in vivo correlation. Release of "mTc-
`EHIDA from matrix tablets (mean ± s.e.m.). Legend:
`• , in vitro (n = 5); o, in vivo (n = 6 (<2 h), 4 (> 2 h)).
`
`33
`
`type of system, but also the osmotic pump
`system for controlled release [15]. This was
`found to have an in vivo 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 before the release of the filled drug
`(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 [16] , 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
`
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`

`34
`
`angular correlation between them. This
`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.
`
`DESTINATION — CHARACTERISTICS OF THE
`GASTROINTESTINAL TRACT
`
`Physiology
`
`The physiology of the gastrointestinal
`tract and the manner in which 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 H2 -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 [19] . Solu-
`tions are emptied rapidly from the stomach,
`as are small particles of less than 1-2 mm
`in diameter [20] . Particles greater than this
`have to be reduced in size by the normal
`digestive process, or if non-digestible, 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,
`
`will empty rapidly from the stomach and can
`be transported through the small intestine to
`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
`
`During the last three years, we have fol-
`lowed the gastrointestinal transit of a variety
`of pharmaceutical formulations (solutions,
`pellets, matrix tablets, osmotic pumps, etc.)
`using the technique of gamma scintigraphy
`[9, 14-16] . 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
`
`MYLAN Ex 1039, Page 8
`
`

`

`Meal
`
`1004,-og_i
`
`St
`
`35
`
`Meal
`
`C-total
`
`N
`
`li
`
`I
`
`\
`
`/
`
`4'130
`.13
`io
`
`60
`
`'E0
`
`4
`
`- (cid:9)
`ti 20
`
`
`ZI
`p A
`i
`0—e-". (cid:9)
`0
`.....4 (cid:9)
`100
`caps uie (cid:9)
`disintegration
`
`i
`200
`
`i (cid:9)
`(cid:9) • (cid:9)
`400 (cid:9)
`300 (cid:9)
`Time (mins)
`
`1.-...'..-----,.....
`
`i (cid:9)
`500 (cid:9)
`
`i
`600 (cid:9)
`
`700
`
`Tc-labelled ion exchange resin 0.9-1.2 mm
`Fig. 6(a). Gastrointestinal transit of pellets (n = 6, mean ± s.e.m.) (cid:9)
`diameter). Legend: •, stomach (St); o, small intestine (SI); 0 , colon (total all regions).
`
`Gastric emptying.
`
`Small intestine transit
`
`Osmotic (cid:9)
`Solution Pellets pumps
`12- (cid:9)
`
`1
`
`Osmotic
`Solution Pellets pumps
`
`1 MIN
`
`15 MIN
`
`30 MIN
`
`1.5 HOUR
`
`4.5 HOUR
`
`9 HOUR
`
`19 HOUR
`
`22 HOUR
`
`27 HOUR
`
`Fig. 6(b). Representative scintiscans showing gastro-
`intestinal transit of pellets.
`
`10
`
`2
`
`as
`
`a
`3.
`<rpmm <ma)
`V) (cid:9)
`
`LL
`
`a
`
`—J
`
`Fig. 7. Gastrointestinal transit of dosage forms.
`Legend: LB --- light breakfast (1500 kJ); HB — heavy
`breakfast (3600 kJ); FA — fasted; SM - standard
`meal. (a) Data from Ref. [26], solution and solid
`(fibre 1- 5 mm in length).
`
`longer) if administered after a heavy
`meal.
`(iii) Small intestine transit is remarkably
`constant and independent of the
`nature of the dosage form or the nutri-
`tional state of the subject.
`(iv) The average small intestine transit time
`is of the order of 3 h ± 1 h.
`(v) Single units can be held for long
`periods (4-12 h) at the ileocaecal valve
`before being moved into the colon.
`
`MYLAN Ex 1039, Page 9
`
`(cid:9)
`(cid:9)
`

`

`36
`
`(vi) The transit pattern for healthy old
`subjects is no different to that for
`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.
`(viii) The transit of delivery systems is
`similar to that of foods in that the
`stomach and not the small intestine
`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.
`There is a clear advantage to be gained if
`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 [271 and the use of
`"mucoadhesives" to delay gastric emptying
`[281. 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 by the size and/or the density of
`the delivery system.
`
`Positioned release of drugs in the colon
`
`The relative constancy of the transit of
`delivery systems in the small intestine can
`be exploited for the design of systems that
`will provide positioned release.
`In certain disease conditions it would be
`advantageous to have the delayed, positioned
`release of a drug in the various regions of the
`colon, following oral administration. The
`use of 5-aminosalicylic acid for the treatment
`of ulcerative colitis is a good example. Release
`of the compound in the small intestine is
`undesirable and can lead to side effects.
`In designing a positioned release system
`one needs to be aware of physiological fac-
`tor(s) that can be exploited to signal the
`release of the dosage form in the intended
`region. For the colon the following possibil-
`ities (and limitations) can be listed:
`(i) pH change (slight and variable).
`(ii) Bacterial flora producing cellulases (over-
`growth in small intestine).
`(iii) Anaerobic conditions (availability of
`suitable redox systems for controlled
`release).
`None of the above is specific enough to
`provide suitable opportunities for an e