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Ina Krögel1 and Roland Bodmeier1 

(1)  College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, GermanyAbstract   Purpose. To develop an enzymatically-controlled pulsatile drug release system based on an impermeable capsule body, which contains the drug and is closed by an erodible pectin/pectinase-plug. Methods. The plug was prepared by direct compression of pectin and pectinase in different ratios. In addition to the disintegration times of the plugs, the lag times and the release profiles of the pulsatile system were determined as a function of pectin:enzyme ratio, the pH of the surrounding medium, and the addition of buffering or chelating agents.Results. The disintegration time of the plug, respectively the lag time prior to the drug release was controlled by the pectin:enzyme ratio and the plug weight. The inclusion of a buffering agent within the plug lead to a plug disintegration independent of the surrounding pH. The addition of Na-EDTA hindered the formation of non-soluble calcium pectinate in the presence of calcium ions in the environment. The addition of effervescent agents to the capsule content resulted in a rapid emptying of the capsule content after plug degradation.Conclusions. A pulsatile drug delivery system based on an erodible pectin plug containing a pectinolytic enzyme was developed. The drug release was controlled by the enzymatic degradation and dissolution of pectin.

controlled drug release - enzymatically-controlled drug release - oral drug delivery - pectin - pulsatile drug release

Roland BodmeierEmail: [email protected]

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SummaryExpert Opinion on Drug DeliveryApril 2009, Vol. 6, No. 4, Pages 441-452 , DOI 10.1517/17425240902895972

Multiple-pulse drug delivery systems: setting a new paradigm for infectious disease therapy

Nitin Saigal , Sanjula Baboota , Alka Ahuja & Javed Ali † Faculty of Pharmacy, Department of Pharmaceutics, Jamia Hamdard, Hamdard Nagar, New Delhi 110 062, India +91 9811 312247; +91 11 2605 9663; [email protected]

† Author for correspondence

Background: Pulsatile drug delivery of actives based on the body's biological rhythms came into sight as a novel and emerging concept in the field of drug delivery. The concept of late has given birth to another field of research worth exploring: multiple-pulse drug delivery. Objective: Delivering a drug in multiple pulses has been applied to antibiotics for effective and patient compliant drug delivery. Delivering antibiotics in divided pulses results in better annihilation of microbes, as it prevents them going into a resistant/dormant stage and developing biological tolerance. The concept appears to have potential, and on 16 March 2009 MiddleBrook™ Pharmaceuticals, Inc. will launch the first of such once-daily product based on their proprietary pulsatile drug delivery technology, PULSYS™. Methods: This review focuses on the rationale, possible strategies and technologies employed for multiple-pulse delivery, as well as current status and future trends. Conclusion: The concept is in its infancy and promises great potential in the fight against microbial resistance; many approved formulations based on similar approaches with new and improved therapeutic paradigms are anticipated in the near future.

Howard N. E. Stevens , , a, Clive G. Wilsona, Peter G. Wellinga, Massoud

Bakhshaeeb, Julie S. Binnsb, Alan C. Perkinsc, Malcolm Frierc, Elaine P.

Blackshawc, Margaret W. Framed, Don J. Nicholsd, Michael J. Humphreyd and

Steve R. Wicksd

a Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street,

Glasgow G4 0NR, UK

b Scherer DDS Ltd, Clydebank, UK

c Department of Medical Physics, Queen's Medical Centre, Nottingham, UK

d Pfizer Central Research, Sandwich, UK

Received 8 January 2001; 

revised 17 December 2001; 

accepted 10 January 2002. 

Available online 30 January 2002.

Abstract

Pulsincap™ formulations designed to deliver a dose of drug following a 5-h delay were

prepared to evaluate the capability of the formulation to deliver dofetilide to the lower

gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well

dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug

absorption to be determined as a function of GI tract site of release. Dofetilide is a well-

absorbed drug, but showed a reduction in observed bioavailability when delivered from

the Pulsincap™ formulations, particularly at more distal GI tract sites. Dispersion of the

drug from the soluble excipient used in this prototype formulation relies on a passive

diffusion mechanism and the relevance of this factor to the reduced extent and

consistency of absorption from the colon is discussed. In these studies the effects of the

degree of dispersion versus the site of dispersion could not be ascertained; nevertheless

the scintigraphic analysis demonstrated good in vitro–in vivo correlation for time of

release from Pulsincap™ preparations. The combination of scintigraphic and

pharmacokinetic analysis permits identification of the site of drug release from the

dosage form and pharmacokinetic parameters to be studied in man in a non-invasive

manner.

Author Keywords: Pulsatile release; Site-release; Gamma scintigraphy;

Pharmacokinetics; Dofetilide; Pulsincap™

Article Outline

1. Introduction

2. Materials and methods 2.1. Preparation of radiolabelled Pulsincap™ dosage forms 2.2. Study design 2.3. Study protocol 2.4. Data analysis

3. Results and discussion 3.1. In vivo study 3.2. Pharmacokinetic analysis 3.3. Correlation of pharmacokinetic and scintigraphic assessment4. Discussion References

Fig. 1. Configuration of Pulsincap™ used in the study.

Fig. 2. GI transit of Pulsincap™ in fasted volunteers (n=27).

Fig. 3. Pharmacokinetic profile, GI transit and scintigraphic release in one subject.

Fig. 4. Dofetilide plasma profiles in a single subject with Pulsincap™ doses released in

small intestine (normalised for time 0=time of first appearance of drug in plasma).

Table 1. Mean (±S.D.) pharmacokinetic parameter values from individual plasma

dofetilide profiles following 1.0 mg solution oral dose (n=10)

r=Correlation coefficient between actual dofetilide plasma profiles and computer

generated profiles based on one compartment pharmacokinetic model.

Table 2. Pharmacokinetic parameter values (±S.D.) for Pulsincap™ formulations as a

function of dose of dofetilide and site of release in the GI tract

Table 3. Dofetilide bioavailability as a function of GI tract site for solution and

Pulsincap™ formulations

Corresponding author. Tel.: +44-141-548-2441; fax: +44-141-552-6443; email:

[email protected]

International Journal of PharmaceuticsVolume 236, Issues 1-2, 2 April 2002, Pages 27-34 Enteric coated timed release systems for colonic targeting

I.R. Wilding , a, S.S. Davisa, F. Pozzib, P. Furlanib and A. Gazzanigab

aPharmaceutical Profiles Ltd, 2 Faraday Building, Highfields Science Park, University

Boulevard, Nottingham NG7 2QP, UK

bZambon Group SpA, Via Lillo del Duca 10, 20091 Bresso Milano, Italy

Received 15 June 1994;  accepted 27 June 1994.  Available online 4 November 2002.

Abstract

The gastrointestinal transit and disintegration characteristics of an enteric coated timed

release formulation were investigated in a group of six healthy volunteers using the

technique of gamma scintigraphy. The mean in vivo tablet disintegration time was

approx. 10 h post-dose and 7.5 h after gastric emptying which was in excellent agreement

with that predicted from in vitro methodology. The anatomical site of release ranged from

the caecum to the descending colon and once the onset of disintegration had been

detected by scintigraphy, the time for complete break up was typically in the region of

45–60 min. The enteric coated Time Clock® system therefore provides for a

pharmaceutical preparation capable of drug delivery to the colon.

Keywords: Timed release; Enteric coating; Gamma scintigraphy; Colon targeting

Evaluation of Pulsincap™ to provide regional delivery of dofetilide to the human GI tract

Howard N. E. Stevens , , a, Clive G. Wilsona, Peter G. Wellinga, Massoud

Bakhshaeeb, Julie S. Binnsb, Alan C. Perkinsc, Malcolm Frierc, Elaine P. Blackshawc,

Margaret W. Framed, Don J. Nicholsd, Michael J. Humphreyd and Steve R. Wicksd

a Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street,

Glasgow G4 0NR, UK

b Scherer DDS Ltd, Clydebank, UK

c Department of Medical Physics, Queen's Medical Centre, Nottingham, UK

d Pfizer Central Research, Sandwich, UK

Received 8 January 2001;  revised 17 December 2001;  accepted 10 January 2002.  Available online 30 January 2002.

Abstract

Pulsincap™ formulations designed to deliver a dose of drug following a 5-h delay were

prepared to evaluate the capability of the formulation to deliver dofetilide to the lower

gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well

dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug

absorption to be determined as a function of GI tract site of release. Dofetilide is a well-

absorbed drug, but showed a reduction in observed bioavailability when delivered from

the Pulsincap™ formulations, particularly at more distal GI tract sites. Dispersion of the

drug from the soluble excipient used in this prototype formulation relies on a passive

diffusion mechanism and the relevance of this factor to the reduced extent and

consistency of absorption from the colon is discussed. In these studies the effects of the

degree of dispersion versus the site of dispersion could not be ascertained; nevertheless

the scintigraphic analysis demonstrated good in vitro–in vivo correlation for time of

release from Pulsincap™ preparations. The combination of scintigraphic and

pharmacokinetic analysis permits identification of the site of drug release from the

dosage form and pharmacokinetic parameters to be studied in man in a non-invasive

manner.

Author Keywords: Pulsatile release; Site-release; Gamma scintigraphy;

Pharmacokinetics; Dofetilide; Pulsincap™

Article Outline

1. Introduction2. Materials and methods

2.1. Preparation of radiolabelled Pulsincap™ dosage forms 2.2. Study design 2.3. Study protocol 2.4. Data analysis

3. Results and discussion3.1. In vivo study 3.2. Pharmacokinetic analysis 3.3. Correlation of pharmacokinetic and scintigraphic assessment

4. DiscussionReferences

1. Introduction

For most immediate release drug formulations, absorption is complete by the time the

swallowed dose has reached the colon and the extent of absorption in the distal gut is of

little consequence. The situation is markedly different when oral sustained or delayed

release formulations are employed, where the extent of absorption is more susceptible to

regional differences in drug absorption and gut transit times. Using scintigraphic

techniques, many studies have demonstrated quantitative differences in the extent and

rate of absorption as the formulation arrives in the distal small intestine and proximal

colon (Wilson and Olsson).

It follows from these observations that a prerequisite for the development of sustained

release dosage form for a specific drug, is a knowledge of the extent of absorption of that

drug throughout the length of the gastrointestinal (GI) tract. In the past, various

experimental methods have been employed to investigate drug absorption in man which

have often involved invasive intubation techniques (Barr; Chan and Vidon) or complex

formulation assemblies ( Gardner et al., 1997).

It has been appreciated for a long time that the intubation process itself can disturb the

normal physiological function of the GI tract and cause any resulting drug absorption

data to be questioned (Read et al., 1983). The formulation approaches employed to date

can be loosely categorised as being either engineering-based or adaptations of classical

formulation technology. The engineering-based systems, which generally rely on an

external stimulus to trigger release from the device, include the HF capsule ( Antonin,

1993), the telemetric capsule ( Lambert et al., 1991) and the Intellisite® capsule (

Gardner and Parr).

The HF capsule has been widely used to study drug absorption (Fuhr; Harder and Staib)

but suffers from the disadvantages that it is only suitable for liquid drug formulations and

requires the use of X-ray to follow GI transit. The Lambert telemetric capsule appears to

be too complex to have gained acceptance, however Intellisite® has been widely

employed and has the advantage that it can be tracked through the GI tract using non-

invasive gamma scintigraphy. It is reported to be suitable for carrying both liquid and

solid formulations, although its consistency in releasing solid drug formulations in the

low-fluid environment of the distal GI tract has been questioned (personal

communication, M.J. Humphrey) and Intellisite is now being superseded by an improved

design, the Enterion Capsule ( Connor et al., 2001).

The most commonly employed formulation systems rely on time-dependent mechanisms

to provoke drug release from capsule devices using gamma scintigraphic techniques to

visualise the site of release. An early prototype capsule device comprised a water

permeable hydrogel capsule in which the internal cavity contained a mixture of drug with

an expanding material; the contents being sealed inside the capsule by a hydrogel plug

(Rashid, 1990). Water diffused through the hydrogel wall inducing swelling of the

contents and expulsion of the plug, causing drug to be released predictably in the colon

after a 5-h mouth to colon transit period ( Wilding et al., 1992).

The Pulsincap™ device (McNeil et al., 1994) (P-CAP) comprises an impermeable

capsule body containing a drug formulation sealed in the capsule with a hydrogel

polymer plug. The plug expands in water or GI tract fluid and slowly exits the capsule

body, releasing the capsule contents after a defined time-delay determined by the length

of the hydrogel plug ( Binns et al., 1993). It has been employed in human studies for

colon targeting ( Bakhshaee; Binns; Wilson; Hebden and Hebden) in timed-release

modes as well as gastroresistant configurations. An alternative version of P-CAP, in

which the hydrogel plug is replaced by an eroding tablet, has been described ( Stevens;

Kr and Ross).

In contrast to the inherent variability associated with the gastric emptying of single unit

dosage forms, transit through the small intestine is reproducible at about 3–4 h (Wilson

and Washington, 1988). With a dosage form releasing purely on a time-basis, it would be

expected to be variably distributed within the GI tract, and thereby permit assessment of

regional absorption from a range of sites. In this study we have used a 5-h delay P-CAP

to deliver dofetilide to different sites in the GI tract, employing scintigraphy and

pharmacokinetic analysis to evaluate its performance in providing regional drug delivery.

Dofetilide was used as the experimental drug, being a weak base (pKa 7.0) with moderate

lipophilicity (log D 0.96 at pH 7.4) and exhibiting linear pharmacokinetics and complete

bioavailability after conventional oral administration (Smith et al., 1992). Dofetilide is a

potent cardiovascular drug and its regional absorption had not previously been explored

and was of interest in the context of future formulation strategies. Three doses were

investigated in the study in order to investigate whether the kinetics of absorption from

distal sites were linearly related to dose.

2. Materials and methods

2.1. Preparation of radiolabelled Pulsincap™ dosage forms

All P-CAP components were supplied by Scherer DDS Ltd and consisted of size 0 gelatin

capsule bodies coated with ethylcellulose (95%) and diethylphthalate (5%). The hydrogel

polymer plug was prepared as rods by cross-linking polyethylene glycol (PEG molecular

weight 8000) using 1,2,6-hexanetriol and dicyclohexylmethane-4,4-diisocyanate. The

cross-linking reaction was catalysed by ferric chloride and the polymer washed in

butylated hydroxyanisole solution (0.025%) before being cut into plugs of appropriate

dimensions to afford a 4–5 h in vitro release time. The devices were assembled in the

Department of Medical Physics, QMC, Nottingham using the configuration in Fig. 1.

Capsules contained lightly compacted powdered sucrose as excipient. A solution of 111In-

DTPA (0.5 MBq) was added to a small quantity of sucrose, dried, and added to the

surface of the sucrose in the capsule. Dofetilide was supplied by Pfizer Central Research,

and weighed (0.25, 0.5 and 1.0 mg) onto the surface of the labelled sucrose in the open

capsule and gently mixed.

Full-size image (6K)

Fig. 1. Configuration of Pulsincap™ used in the study.

2.2. Study design

An open, four-way crossover study in which male fasted subjects were dosed on four

occasions with an interval of 7 days between dosing. In addition to the three doses of

dofetilide administered from P-CAP, each subject also received dofetilide (1 mg) as a

solution. Eleven subjects entered the study. The study conformed to the Declaration of

Helsinki and the protocol was reviewed and approved by the local ethics committee at the

University of Nottingham Medical School. ARSAC approval was obtained prior to

initiation of the study.

2.3. Study protocol

On the study day, volunteers arrived in the Department of Medical Physics, QMC, having

fasted from 21:00 h the previous evening. Anterior and posterior markers containing a

small amount of 111In label were taped to the abdomen of each volunteer, above the

hepatic flexure, to allow accurate alignment of sequential images. Between 7.30 and 9.00

a.m., each volunteer ingested either a P-CAP with 240 ml water or a solution of 1 mg

dofetilide dissolved in the same volume of water. Using a single headed gamma camera

fitted with a medium energy collimator, serial anterior and posterior static scintigraphic

images of 30 s duration were taken immediately following administration and at 15 min

intervals around the expected time of drug release as well as at longer intervals

throughout the day. The subjects remained fasted until the first meal at 4 h post dosing,

followed by a second standard meal at dose+11 h.

Following each imaging interval a blood sample (5 ml) was taken from a forearm vein,

plasma was separated, and dofetilide concentrations in plasma were determined by

validated radioimmunoassay (Walker et al., 1991). The analytical method was chosen for

unchanged dofetilide and response was linearly related to dofetilide concentrations in

plasma with a lower limit of detection of 50 pg/ml, with inter-assay variability ranging

from 5–18% over the assay range.

2.4. Data analysis

From the scintigraphic analysis, the time of gastric emptying, arrival at the ileocaecal

junction and entry into the colon were recorded. The time of capsule opening, as

determined by spreading of radiolabel in the GI tract contents, was determined by

examination of the scintiscans. Pharmacokinetic parameter values (Cmax, Tmax, AUC(0–48 h))

and elimination T1/2 from the solution dose of dofetilide were determined by fitting

individual plasma data sets to the pharmacokinetic one-compartmental model with first

order drug input and output using software WinNonlin Version 3. Following the P-CAP

0.25, 0.5 and 1.0 mg doses, plasma dofetilide profiles did not lend themselves to

pharmacokinetic modelling and pharmacokinetic parameter values were determined

directly from observed data.

3. Results and discussion

3.1. In vivo study

Eight subjects completed the study receiving all four treatments. One subject received the

1.0 mg solution dose only, and one subject the solution and 0.25 mg P-CAP doses only.

One subject received just the 0.25 and 0.5 mg P-CAP doses.

GI transit rate data are summarised in Fig. 2. Gastric emptying of the P-CAP

formulations was generally rapid, although one capsule remained in the stomach for the

duration of the study. Small intestinal transit, arrival at the ileocaecal junction, and entry

into the colon compared favourably with literature values for non-disintegrating

formulations. Site of release of drug and scintigraphic marker into the GI tract varied,

with one capsule being retained in the stomach and the others being distributed along

different regions of the GI tract (small intestine (9), ileocaecal junction (7) and colon

(10)).

Full-size image (6K)

Fig. 2. GI transit of Pulsincap™ in fasted volunteers (n=27).

3.2. Pharmacokinetic analysis

Results of pharmacokinetic analysis of the dofetilide solution data are given in Table 1

and the data for the P-CAP doses is shown in Table 2 as a function of dofetilide dose and

site of release.

Table 1. Mean (±S.D.) pharmacokinetic parameter values from individual plasma

dofetilide profiles following 1.0 mg solution oral dose (n=10)

Full-size table (2K)

r=Correlation coefficient between actual dofetilide plasma profiles and computer generated profiles based on one compartment pharmacokinetic model.

Table 2. Pharmacokinetic parameter values (±S.D.) for Pulsincap™ formulations as a

function of dose of dofetilide and site of release in the GI tract

Full-size table (11K)

An excellent fit was obtained by the ascribed one compartment open model with first

order absorption and elimination to individual plasma data sets following the solution 1.0

mg dose. The mean correlation coefficient of goodness of fit of observed data to model

values was 0.97. Following the solution dose, a mean peak dofetilide concentration of 6.4

ng/ml was obtained at 1.7 h. There was no absorption lag-time. Elimination of dofetilide

from plasma, after peak plasma levels have been reached, occurred with a half-life of 6 h.

The mean AUC(0–48 h) was 75 ng h/ml.

Plasma concentrations following P-CAP doses were consistently lower than from the 1

mg solution dose. The expected lag-time of approximately 5 h occurred before dofetilide

could be detected at a measurable concentration in plasma. Subsequent absorption of

dofetilide was generally prolonged with mean Tmax values in the range 5.5–14 h being

determined (Table 2). Both the Cmax and AUC(0–48 h) were related to the dofetilide P-CAP

doses administered, but were not dose proportional.

Inter-individual variability in plasma dofetilide levels was similar from solution and P-

CAP treatments. Among pharmacokinetic parameters, variability in Cmax, Tmax were

similar from solution and P-CAP, but variability in AUC(0–48 h) values tend to be greater

for the P-CAP administrations (Table 1 and Table 2).

3.3. Correlation of pharmacokinetic and scintigraphic assessment

Dispersion of the marker was easy to ascertain in sequential scintigraphic images

although since blood sampling and imaging are not carried out simultaneously, there is

naturally a small time shift error of no more than ±0.25 h associated with measurements.

Good concordance was noted for the observed release of activity in 24/27 subjects

available for analysis, with a mean scintigraphic release time of 5.3±1.5 h. In three

subjects, blood levels were detected prior to visualisation of scintigraphic dispersion. Fig.

3 shows a typical pattern of release for a subject who had been administered P-CAP

containing 0.5 mg of dofetilide.

Full-size image (4K)

Fig. 3. Pharmacokinetic profile, GI transit and scintigraphic release in one subject.

Although absorption of dofetilide from solution dose was immediate and rapid,

absorption from P-CAP did not occur until after the expected approximately 5 h, by

which time the dosage form was dispersed to various GI tract sites. Absorption of

dofetilide from the P-CAP was observed from all GI sites, however, absorption was

generally prolonged from distal sites. Where P-CAP doses were released in the proximal

intestine, the observed plasma profiles were generally more consistent with the data for

the oral solution (Fig. 4).

Full-size image (3K)

Fig. 4. Dofetilide plasma profiles in a single subject with Pulsincap™ doses released in

small intestine (normalised for time 0=time of first appearance of drug in plasma).

The extent of absorption from the different GI tract sites for P-CAP is compared to the

oral solution (Table 3) following normalisation of the P-CAP AUC values to equivalent

1.0 mg dofetilide doses. The data show a reduction in bioavailability of dofetilide from P-

CAP irrespective of GI tract site of release, with release in the colon showing lowest

bioavailability, indicating that the overall absorption of dofetilide was less efficient for

the time-delayed P-CAP formulations than from solution.

Table 3. Dofetilide bioavailability as a function of GI tract site for solution and

Pulsincap™ formulations

Full-size table (6K)

4. Discussion

Low and prolonged levels of dofetilide following P-CAP administrations imply that

either release of drug from the preparations was not instantaneous following capsule

opening, or that absorption of dofetilide from the distal regions of the intestinal tract is

less efficient than from the stomach and proximal small intestine. In part this may be due

to sluggish agitation in the distal gut which compounds the loss of bioavailability due to a

reduced surface area and decreased paracellular transport.

Scintigraphic images from the study show that when the unit releases in the stomach,

small intestine or ICJ, there is a marked increase in dispersion of the marker compared to

when the unit releases in the ascending or transverse colon. This leads to a trend of

increased dofetilide absorption from those proximal sites as illustrated in Table 3. In one

subject the unit remained in the stomach for a prolonged period of time. This observation

is not unusual and reflects the absence of migrating myoelectric potentials (housekeeper

waves) when subjects are fasted. The rhythm of Phase III is usually established by late

mid-morning but can be erratic. The subsequent intake of a lunchtime meal will prevent

the emptying of large non-disintegrating objects, such as the size 0 capsule employed in

this study.

The drug formulation employed in this study comprises dofetilide distributed onto a

soluble excipient that becomes exposed to GI tract fluid after the capsule opens. As fluid

enters, dofetilide may dissolve and either empty rapidly from the capsule resulting in a

high Cmax and a short Tmax (e.g. at upper GI tract sites where motility and fluid volume is

maximised and viscosity minimised) or, alternatively, may diffuse further into the

capsule and become dispersed throughout the sucrose excipient and released only

progressively, resulting in a lower Cmax and a prolonged Tmax (e.g. at lower GI tract sites

where motility is reduced and fluid is less available and more viscous). In other studies

with P-CAP preparations, in contrast to the soluble excipient fill employed here, the use

of rapidly expansive excipient fills have been shown to be highly effective in expelling

drug from the opened capsule (Stevens et al., 1999).

With the P-CAP configuration evaluated in this study it is possible that in the colon there

is insufficient water to cause rapid dissolution and additionally the sluggish stirring

provided by the haustral movements may limit dispersion of the fill. Similarly, the

importance and difficulties surrounding the dissolution process in the low-fluid

environment within the colon have been highlighted by Takaya et al. (1998) with studies

on rupturable capsule formulations.

In other studies with the P-CAP dosing form, we set out to deliver more distally and in

order to accomplish this the unit was modified by attaching the drug formulation to the

back of the hydrogel plug such that it was pulled out during plug ejection. This approach

allowed the mapping of regional differences in quinine absorption (Hebden et al., 1999b)

and to investigate the effects of manipulating lumenal water on quinine absorption in the

colon ( Hebden et al., 1999a). These data, like those presented in the present study show

that pulse delivery more distally may result in a diminution in the extent of absorption.

However, whether this arises because of reduced permeability of the drugs concerned in

the colon or of impeded dispersion from the formulation, remains to be determined.

In spite of these reservations, the data obtained from the study in human volunteers

demonstrate that the Pulsincap™ delivery system has a role as a convenient probe device

and is capable of providing time-delayed release of drug substance within the GI tract.

Utilising this approach coupled with gamma scintigraphy, pharmacokinetic parameters

can be explored from a range of GI tract sites in man in a non-invasive manner.

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[email protected]

International Journal of PharmaceuticsVolume 236, Issues 1-2, 2 April 2002, Pages 27-34 Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles

T. Bussemer and R. Bodmeier ,

College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169, Berlin, Germany

Received 7 April 2003;  revised 15 July 2003;  accepted 31 July 2003. ; Available online 16 October 2003.

Abstract

The objective of this study was to develop and evaluate a rupturable pulsatile drug

delivery system based on soft gelatin capsules with or without a swelling layer and an

external water-insoluble but -permeable polymer coating, which released the drug after a

lag time (rupturing of the external polymer coating). The swelling of the gelatin capsule

itself was insufficient to rupture the external polymer coating, an additional swelling

layer was applied between the capsule and the polymer coating. Croscarmellose sodium

(Ac-Di-Sol) was more effective as a swelling agent than low and high molecular weight

hydroxypropylmethyl cellulose (HPMC; E5 or K100M). Brittle polymers, such as ethyl

cellulose (EC) and cellulose acetate propionate (CAPr), led to a better rupturing and

therefore more complete drug release than the flexible polymer coating, Eudragit RS. The

lag time of the release system increased with higher polymer coating levels and decreased

with the addition of a hydrophilic pore-former, HPMC E5 and also with an increasing

amount of the intermediate swelling layer. The water uptake of the capsules was linear

until rupture and was higher with CAPr than with EC. Soft gelatin capsule-based systems

showed shorter lag times compared to hard gelatin capsules because of the higher

hardness/filling state of the soft gelatin capsules. The swelling pressure was therefore

more directed to the external polymer coating with the soft gelatin capsules. Typical

pulsatile drug release profiles were obtained at lower polymer coating levels, while the

release was slower and incomplete at the higher coating levels. CAPr-coated capsules

resulted in a more complete release than EC-coated capsules.

Author Keywords: Gelatin capsules; Lag time; Mechanical properties; Oral drug

delivery; Polymeric films; Pulsatile release; Swelling agents

Article Outline

1. Introduction

2. Materials and methods2.1. Preparation of polymer films 2.2. Mechanical properties of polymer films in the dry and wet state 2.3. Preparation of the pulsatile release soft gelatin capsules 2.4. Lag time and drug release 2.5. Water uptake studies 2.6. Hardness of the pulsatile release soft gelatin capsules

3. Results and discussionReferences

1. Introduction

Most oral extended release drug delivery systems (DDS) release the drug continuously in

a linear or non-linear fashion. Pulsatile drug release profiles are interesting for the

treatment of several diseases including hypertension, bronchial asthma, myocardial

infarction, angina pectoris, rheumatic disease, and ulcer disease ([Bussemer et al., 2001

and Ritschel and Forusz, 1994]). Pulsatile release DDS allow the adaptation of drug

therapies to chronopharmacological needs ( [Lemmer, 1991 and Lemmer, 1999]).

Pulsatile drug release was obtained with drug-containing cores layered with erodible

coatings, which released the drug after erosion of the coating ([Gazzaniga et al., 1994]).

Alternatively, rupturable dosage forms, such as the time-explosion system, were

investigated, whereby pellets with a swellable hydroxypropylcellulose layer were coated

with a water-insoluble polymer layer, which ruptured after a lag-time and then released

the drug ( [Ueda et al., 1994a, Ueda et al., 1994b and Ueda et al., 1994c]). However, the

drug loading of pellets is limited and liquid fillings are not possible.

Various capsule-shaped pulsatile delivery systems have been described using

insoluble/impermeable and hard capsule halves with swellable plugs, e.g. the Pulsincap

system ([Binns et al., 1996, McNeill et al., 1990 and Wilding et al., 1992]). One

drawback of this system was the use of a non-approved plug material, which was

overcome, e.g. by the use of erodible plugs ( [Krogel and Bodmeier, 1998]) or

biocompatible materials ( [Krogel and Bodmeier, 1999a and Krogel and Bodmeier,

1999b]; [Tsume et al., 2000]). The manufacturing process was still difficult and was

conducted manually.

Capsules are pharmaceutically elegant dosage forms offering an improved drug stability,

because the content is tightly enclosed by the capsule shell and thus protected from

oxygen, moisture and light, and also from physiological fluids until the drug is released.

Hard capsules are usually filled with solid materials ([Fahrig and Hofer, 1998]), but some

drugs require a liquid formulation for solubility or bioavailability reasons ( [Savio et al.,

1998]). The filling of semisolids or liquids into hard gelatin capsules is possible

( [Bowtle, 1998 and Stegemann, 1999]).

A pulsatile delivery system based on hard gelatin capsules with a solid content has been

recently described ([Bussemer et al., 2003a]). The capsules were coated with a swelling

layer followed by an external polymer coating, which ruptured after a certain lag time,

induced by the water uptake/swelling pressure of the swelling layer.

The objective of this study was to develop and evaluate a soft gelatin capsule-based

pulsatile release system for the delivery of liquid drug contents. The performance was

compared to the pulsatile hard capsules.

2. Materials and methods

Ammonio methacrylate copolymer type B, USP 25 (Eudragit® RS, Röhm Pharma,

Darmstadt, Germany), ethyl cellulose (EC; Ethocel® Standard 10, Dow Chemical

Company, Midland, MI, USA), cellulose acetate propionate (CAPr; CAP 504-0.2,

Eastman Chemical Company, Kingsport, TN, USA), hydroxypropylmethyl cellulose

(HPMC; Methocel® E5 or K100M, Colorcon, Orpington, UK), triethyl citrate (TEC;

Morflex, Greensboro, NC, USA), croscarmellose sodium (Ac-Di-Sol®, FMC, Newark,

DE, USA), polyvinyl pyrrolidone (Kollidon® 30, BASF, Ludwigshafen, Germany), soft

gelatin capsules (length 12.6 mm, width 8 mm, filled with 50 mg methylene blue in PEG

400) (R.P. Scherer, Eberbach, Germany).

All other reagents were of analytical grade and were used without further purification.

2.1. Preparation of polymer films

Polymer films were produced by casting of 10% (w/w) polymer solutions in 90 vol.%

ethanol onto a Teflon plate using a casting knife (Multicator 411, Erichsen, Hemer,

Germany). After drying for 24 h under a special cover to reduce solvent evaporation in

order to obtain smooth homogeneous film surfaces, the films were removed and the film

thickness was measured at five points with a thickness gauge Minitest 600 (Erichsen,

Hemer, Germany).

2.2. Mechanical properties of polymer films in the dry and wet state

Polymer film samples of 6.5 cm×6.7 cm were fixed in a special Teflon holder with

several holes (n=3). The holder with the film was then immersed into 0.1 N HCl at 37 °C.

The puncture strength of films was measured with an Instron 4466 (Instron Wolpert,

Darmstadt, Germany). A metal probe, diameter 5 mm, length 15 cm, was driven with a

speed of 5 mm/min through a hole either in the dry state (initial puncture strength) or

after 60 min on films immersed in the release medium. Force (N)–displacement (mm)

curves were recorded with an Instron load cell. The following parameters were

calculated:

Modulus=slopeoftheforce–displacementcurvebeforefilmbreak

A detailed description of the puncture

test has been described ([Bodmeier and Paeratakul, 1993 and Bodmeier and Paeratakul,

1994]).

2.3. Preparation of the pulsatile release soft gelatin capsules

Pulsatile capsules were prepared by layering of a 12% (w/w) suspension of Ac-Di-Sol in

a 4% (w/w) solution of Kollidon 30 in isopropanol onto soft gelatin capsules in a GC-300

Glatt drum coater (swelling layer) (prewarming of capsules at 40 °C for 10 min, spray

nozzle diameter 1.2 mm, atomizing air pressure 0.8 bar, air flow rate 110 m3/h, inlet air

temperature 40 °C, product temperature 25–28 °C, spray rate 10–12 g/min, rotational pan

speed 15 rpm, post-coating drying at 35 °C for 10 min). In a second step, the polymer

coating was applied from a 4% (w/w) polymer solution in 90 vol.% ethanol. With HPMC

as a pore former, EC was first dissolved in 96 vol.% ethanol, then HPMC was dispersed,

and finally water was added slowly under stirring until a clear solution was obtained. The

EC solutions were applied in the GC-300 Glatt drum coater under the conditions

described above.

2.4. Lag time and drug release

The lag time was determined by visual observation of the pulsatile capsules in a USP 25

paddle apparatus (medium: phosphate buffer USP, pH 7.4, 37 °C, rotation speed

100 rpm) and was defined as the time point, when the outer coating ruptured (n=5). The

amount of methylene blue released was studied by withdrawing 3 ml samples at

predetermined time points. The samples were measured after appropriate dilution with a

Shimadzu UV-2101PC UV-Vis scanning spectrophotometer (Shimadzu Europe,

Duisburg, Germany) at a wavelength of 663 nm.

2.5. Water uptake studies

At predetermined time points after exposure of the pulsatile capsules to phosphate buffer

USP, pH 7.4 (37 °C, 50 ml-flask, shaker-incubator at 50 rpm), the capsules were

carefully blotted with tissue paper to remove the surface water and then were weighed

with an analytical balance (n=3). Water uptake was calculated as follows:

2.6. Hardness of the pulsatile release soft gelatin capsules

Capsules, optionally after incubation in phosphate buffer USP, pH 7.4 at 37 °C, were

fixed on a metal plate. A metal probe connected to the Instron 4466 was positioned on the

surface of the capsules. The metal probe was then moved downward at a constant speed

of 5 mm/min. The maximum force was the force when the coating of the capsule cracked.

It was defined as the hardness of the capsules.

3. Results and discussion

Preliminary studies were needed to select a suitable polymer for the polymer coating of

the pulsatile capsules. The outer polymer coating has to be water-permeable and has to

rupture completely after the lag time. Besides the water permeability ([Rhodes and

Porter, 1998]), the mechanical properties of the coating are therefore an important

characteristic of the system. The mechanical properties of polymer films, which were

prepared by casting from ethanolic solutions, were investigated in the dry and the wet

state ( Table 1). The mechanical parameters—puncture strength, modulus, strain and

energy—decreased after incubation of the films in the medium. This could be explained

by the uptake of water, which acted as a plasticizer ([Bodmeier and Paeratakul, 1993 and

Tho et al., 1999]). The Eudragit RS-film was very flexible and soft, as indicated by a high

strain (elongation) and a low modulus in both the dry and wet state. The EC films had a

much lower strain with a higher modulus. The most brittle film was an EC/HPMC-

combination as indicated by its low puncture strength accompanied with a low strain and

low energy required to rupture the film. The mechanical properties of CAPr-containing

films could not be investigated in this study. CAPr formed very brittle films, which could

not be removed from the Teflon plates without breakage. However, since the mechanical

properties of CAPr films were described as brittle ( [Edgar et al., 2001, Sand, 1990 and

Schauber et al., 1999]), it was included in the coating experiments.

Table 1. Mechanical properties of polymeric films, cast from ethanolic solutions

Full-size table (14K)

Not-found: mean.

In a first coating experiment, soft gelatin capsules were coated with Eudragit RS. The

coated capsules significantly increased in volume after incubation in the release medium

(Fig. 1). A big oil droplet was visible inside the capsule, the rest of the capsule was filled

with water. The swollen capsules were also very soft. Because of the flexibility of the

Eudragit RS coating, the coated capsules ruptured only slightly with very small cracks

and did not rupture completely. No significant drug release was determined. Eudragit RS

was therefore not suitable as a coating in this application. The less flexible and more

brittle polymers, EC and CAPr, were evaluated for future coatings. Both polymers are

soluble in ethanol and were directly sprayed on the soft gelatin capsules.

Full-size image (12K)

Fig. 1. Eudragit RS-coated soft gelatin capsules. Left: original capsule in the dry state;

right: capsule after 4 h of incubation in the release medium (phosphate buffer, pH 7.4).

EC- or CAPr-coated soft gelatin capsules did not expand much in size and did therefore also not rupture sufficiently. Only small amounts of the dye, methylene blue, which served as a model drug, was released from the capsules. In addition, the slope of the lag

time-coating level profile was relatively steep, which indicated a high sensitivity in the lag time to small changes in the coating level, as shown for an EC/HPMC 80:20-combination (Fig. 2). The lag time prior to drug release increased with increasing coating level (thickness of the polymeric coating). The lag time was lower for plasticizer-free systems compared to capsules coated with EC/HPMC plasticized with 20% (w/w) TEC. The plasticizer-containing coating was more flexible and resisted an increasing inner pressure for a longer time.

Full-size image (5K)

Fig. 2. Lag time of coated soft gelatin capsules without swelling layer.

The swelling forces developed by the soft gelatin capsule shell were not strong enough to rupture the outer polymer coating completely in order to assure a rapid and complete drug release. Therefore, an additional swelling layer was introduced between the capsule shell and the polymer coating. After contact with release media, the water penetrates through the polymeric coating, the swelling layer hydrates and swells and finally ruptures the outer coating completely. The gelatin shell then disintegrates and releases the drug rapidly.

Various excipients were tested as possible swelling layers. The application of HPMC E5

as a swelling layer reduced the lag time (Fig. 3), but did not improve the rupture behavior

enough, the capsules were still incompletely ruptured. The higher molecular weight

HPMC K100M resulted in an increase in the lag time because it built a strong gel, which

retarded the water uptake, thus prolonging the swelling and rupturing process.

Full-size image (5K)

Fig. 3. Lag time of coated soft gelatin capsules with HPMC swelling layer. Polymer

coating: EC/HPMC (80:20), 20% TEC, swelling layer: HPMC E5 or K100M, 6–

9 mg/cm2.

Next, the highly swellable superdisintegrant, Ac-Di-Sol (croscarmellose sodium), was

tested. Ac-Di-Sol was chosen because it showed the best swelling performance in a series of superdisintegrants ([Bussemer et al., 2003b]). Ac-Di-Sol was not soluble in organic solvents, it was therefore sprayed from an ethanolic suspension, containing Kollidon 30 (PVP) as a dissolved binder. The resulting swelling layer was mechanically stable towards attrition.

The Ac-Di-Sol-based swelling layer resulted in good rupturing of the polymer coating.

Increasing the amount of swelling layer resulted in reduced lag times at the same external

polymer coating level (Fig. 4). As expected, the lag time also increased with increasing

coating level because of a reduced permeability of the EC coating for the release medium

and the increased mechanical resistance. The extent of rupturing of the outer polymer

coating in general decreased at higher polymer coating levels because of the increased

mechanical strength of the external polymer coating.

Full-size image (5K)

Fig. 4. Lag time of coated soft gelatin capsules with an Ac-Di-Sol swelling layer.

Polymer coating: EC/HPMC (80:20), 20% TEC, swelling layer: Ac-Di-Sol:Kollidon 30

(75:25).

The water permeability of the outer EC layer can be varied by the inclusion of a low molecular weight HPMC. Increasing the HPMC E5 amount in the external coating decreased the lag time (Fig. 5). The water influx increased due to the formation of water-filled channels in the EC-membrane ([Gunder et al., 1995 and Hjartstam and Hjertberg, 1998]). Water reached the swelling layer faster and the expansion of the swelling layer was accelerated, thus shortening the lag time prior to rupture. Additionally, the puncture strength as well as the energy, necessary to rupture the film, also decreased with increasing HPMC content ( Table 1). The lag time-coating level profile became flatter, indicating a lower sensitivity of the lag time to variations in the coating level and therefore an improved robustness of the system.

Full-size image (6K)

Fig. 5. Lag time of soft gelatin capsules as a function of EC/HPMC ratio. Polymer

coating: EC/HPMC, different ratios, 20% TEC, swelling layer: Ac-Di-Sol:Kollidon 30

(75:25), 26.9 mg/cm2.

The trends in the results observed with EC were also obtained with CAPr, another cellulose-based polymer (Fig. 6). The lag time increased with the use of the plasticizer TEC due to the higher flexibility of the coating and it decreased with the addition of the pore-former HPMC. When compared to EC, the lag times were shorter with CAPr, probably because of the higher water permeability of this polymer. For example, at a HPMC level of 40%, the lag phase was very short with CAPr.

Full-size image (7K)

Fig. 6. Lag time of CAPr-coated soft gelatin capsules. Polymer coating: different CAPr-

formulations, swelling layer: Ac-Di-Sol:Kollidon 30 (75:25), 23.7–27.9 mg/cm2.

Water uptake studies on the coated capsules confirmed the higher water permeability of the CAPr coatings compared to the EC coatings (Fig. 7). The curves showed an almost linear water uptake until the polymer coating ruptured. The rate of water uptake decreased with increasing polymer coating level. In all cases, the maximum water uptake was very similar, and was between 11.4 and 11.8% (w/w) for the EC/HPMC-combination (Fig. 7A) and between 12.4 and 14.2% (w/w) for the CAPr/HPMC-combination ( Fig. 7B). The maximum water uptake value was slightly higher at the higher coating level because of the higher mechanical resistance of the thicker coatings.

Full-size image (10K)

Fig. 7. Water uptake of coated soft gelatin capsules. Polymer coating: (A) EC/HPMC

(80:20), 20% TEC; (B) CAPr:HPMC (80:20), 20% TEC, swelling layer: Ac-Di-

Sol:Kollidon 30 (75:25), 26.9 mg/cm2.

Alternatively to soft gelatin capsules, which are primarily used for the delivery of liquids, hard gelatin capsules were also investigated in this study. The structure of the delivery

system was the same in both cases, a soft or hard gelatin capsule core, a swelling layer and a layer of a water-insoluble but -permeable polymer coating.

The lag time was longer with hard gelatin than with soft gelatin capsules at the same

coating level, both having the same composition of the swelling and coating layer (Fig.

8). The reason for the shorter lag times with the soft gelatin capsules resides in the

different degree of fillings of hard and soft gelatin capsules. Soft gelatin capsules are

completely filled with liquid, the pressure developed by the swelling layer is therefore

directed primarily towards the outer polymer layer. In comparison, hard gelatin capsules

are not completely filled with powder, there is air inside the capsule. The pressure of the

swelling layer is therefore also directed towards the capsule core and not exclusively

towards the outer coating. More water has therefore to be taken up by the hard gelatin

capsules resulting in longer lag times at the same coating level. This was also confirmed

with hardness data of soft and hard gelatin capsules (Fig. 9). Soft gelatin capsules were

approximately four times harder than the hard capsules (values at time 0). The hardness

of the soft gelatin capsules declined with increasing incubation time, while the hardness

of the hard gelatin capsules could not be detected in the wet state, because the wet

capsules were squeezed under the moving punch without giving a measurable signal. As

mentioned above, the higher hardness of soft gelatin capsules was caused by the higher

thickness of the gelatin shell as well as by the complete filling and the absence of air

when compared with hard gelatin capsules.

Full-size image (8K)

Fig. 8. Comparison of lag times of coated hard (HGC) and soft gelatin capsules (SGC).

Polymer coating: CAPr with and without HPMC, 20% TEC, swelling layer: Ac-Di-

Sol:Kollidon 30 (75:25), 21.2 mg/cm2.

Full-size image (4K)Fig. 9. Hardness of soft and hard gelatin capsules after incubation in the release medium (phosphate buffer, pH 7.4).

Fig. 10 shows the drug release of individual soft gelatin capsules coated with EC/HPMC (60:40), plasticized with 20% TEC. The formulation with a low coating level of 3.2 mg/cm2 showed distinct pulsatile release profiles, with a rapid and complete drug release after the lag time. However, at a higher coating level, the drug release was not complete. The capsules did not rupture completely, only smaller cracks were visible. This was caused by the higher mechanical resistance of the thicker coatings. This behavior seemed to be more a problem with the soft gelatin capsules than with hard gelatin capsules ([Bussemer et al., 2003a]) because of the thicker gelatin shell, which had a longer disintegration time when the outer polymeric coating was still partially present, even after it was ruptured. One solution for a better rupturing could also be the use of a thicker swelling layer providing a higher swelling pressure.

Full-size image (10K)

Fig. 10. Drug release from coated soft gelatin capsules as a function of ethyl cellulose

coating level. Polymer coating: EC/HPMC (60:40), 20% TEC, swelling layer: Ac-Di-

Sol:Kollidon 30 (75:25), 23.2 mg/cm2.

With CAPr, the drug release profiles were similar (Fig. 11). Again, at low coating levels, corresponding to lag times up to 3 h, the release was rapid after rupture of the polymer coating. With higher coating levels, the release rate was reduced and in some cases it was incomplete. However, the CAPr-coated capsules performed better than the EC-coated capsules. Another reason for the slow in vitro release could be the lower agitation and the absence of peristaltic movement and destructive forces in the dissolution apparatus, which are present under in vivo conditions and which would result in a more complete drug release after rupturing.

Full-size image (23K)

Fig. 11. Drug release from coated soft gelatin capsules as a function of cellulose acetate

propionate coating level. Polymer coating: (A) CAPr, (B) CAPr, 20% TEC, (C)

CAPr:HPMC (80:20), 20% TEC, swelling layer: Ac-Di-Sol:Kollidon 30 (75:25),

26.7 mg/cm2.

In conclusion, a pulsatile release system based on soft gelatin capsules, was developed with pulsatile drug release profiles, whereby the lag time was primarily controlled by amount and composition of the swelling layer and the coating layer, which affected the swelling pressure of the swelling layer and the water permeability and mechanical properties of the external polymer coating.

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International Journal of PharmaceuticsVolume 267, Issues 1-2, 28 November 2003, Pages 59-68

Mechanisms of dissolution of frusemide/PVP solid dispersions C. Dohertya and P. York , a

aPostgraduate School of Studies in Pharmacy, University of Bradford U.K.

Received 21 April 1986; 

revised 30 June 1986; 

accepted 21 July 1986. 

Available online 5 November 2002.

Abstract

With a discriminating intrinsic dissolution apparatus the dissolution rates and profiles of frusemide-

polyvinylpyrrolidone (PVP) mix and solid dispersion systems (10–100% w/w frusemide) have been

examined together with scanning electron photomicrographs (SEM) of the dissolution surfaces of

compressed discs before and after dissolution. Solid dispersion systems exhibited higher dissolution rates

than corresponding mixes and untreated frusemide. The peak intrinsic dissolution rate, found for both mix

and dispersion systems containing 40% w/w frusemide, was attributed to a balance of two opposing factors.

In mix systems a dissolution-promoting effect of soluble complex formation with PVP is balanced by a

viscosity-related retarding effect of increasing PVP content in the diffusion layer. In dispersion systems a

large dissolution-promoting effect of the X-ray amorphous state of the drug at the 40% drug level produces a

highly supersaturated diffusion layer demonstrated in time/solubility profiles which is also balanced by the

increasing PVP content in the diffusion layer. These findings were further supported by the observed

dependence of the dissolution rate on the molecular weight and related solution viscosity of the PVP used to

form the X-ray amorphous solid dispersion and mechanical mix, in high polymer content systems. In

addition, a filming effect over dissolved compact faces shown by SEM, when the drug level was 40% w/w or

less was attributed to a PVP layer covering the dissolving face and the change from a crystalline drug-

controlled dissolution mechanism to a polymer controlled system.

Keywords: Solid dispersion; Mechanisms of dissolution; Amorphous state; Supersaturation phenomena;

Soluble complex; PVP retarding effect

Correspondence: P. York, Postgraduate School of Studies in Pharmacy, University of Bradford, Bradford,

West Yorkshire BD7 1DP, U.K..

International Journal of PharmaceuticsVolume 34, Issue 3, January 1987, Pages 197-205