Depot Formulation5

7/31/2019 Depot Formulation5

1/15

Review

A lipid based depot (DepoFoam1 technology) for

sustained release drug delivery

Sankaram Mantripragada*

SkyePharma Inc., 10450 Science Center Drive, San Diego, CA 92121, USA

Accepted 18 February 2002

Abstract

Encapsulation of drugs into multivesicular liposomes (DepoFoam1) offers a novel approach to sus-

tained-release drug delivery. While encapsulation of drugs into unilamellar and multilamellar liposomes,

and complexation of drugs with lipids, resulted in products with better performance over a period lasting

several hours to a few days after intravascular administration, DepoFoam-encapsulation has been shown

to result in sustained-release lasting over several days to weeks after non-vascular administration. The

routes of administration most viable for delivery of drugs via DepoFoam formulations include intrathecal,

epidural, subcutaneous, intramuscular, intra-atricular, and intraocular. DepoFoam particles are dis-

tinguished structurally from unilamellar vesicles, multilamellar vesicles, and neosomes in that each particle

comprises a set of closely packed non-concentric vesicles. The particles are tens of microns in diameter and

have large trapped volume, thereby affording delivery of large quantities of drugs in the encapsulated form

in a small volume of injection. A number of methods based on a manipulation of the lipid and aqueous

composition can be used to control the rate of sustained-release from a few days to several weeks. # 2002

Elsevier Science Ltd. All rights reserved.

0163-7827/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.P I I : S 0 1 6 3 - 7 8 2 7 ( 0 2 ) 0 0 0 0 4 - 8

Progress in Lipid Research 41 (2002) 392406www.elsevier.com/locate/plipres

Contents

1. Introduction ................................................................................................ ........................................................... 393

1.1. Structure ........................................................................................................................................................ 394

2. Method of preparation................................................................................................ ........................................... 397

3. Methods for controlled release............................................................................................................................... 399

* Tel.: +1-858-625-2424; fax: +1-858-678-3982.

E-mail address: [email protected]


2/15

1. Introduction

In the area of injectable drug delivery systems, research into liposomes played a major role in

the past few decades. Significant efforts in basic and applied research institutions led to the clin-

ical development and ultimate approval by regulatory agencies for human use of a lipid complex

(Abelcet1, Amphotec1) and three liposome formulations, AmbiSome1, DaunoXome11 and a

Stealth

1

liposome (DOXIL

1

) [1,2]. These products have been developed for intravascularadministration. The advantages conferred by the lipid complex, liposome and Stealth1 liposome

technologies include enhancement of circulation times, and reduced toxicity by lipid encapsulation.

This article reviews the scientific basis of DepoFoam1 technology, a lipid-based drug delivery

system. A sustained release depot product (DepoCyt1) utilizing this technology has been clini-

cally developed and recently approved for clinical use by regulatory agencies [3]. DepoFoam

formulations of drugs are intended for non-vascular, but parenteral administration of drugs by

injection. In the published scientific literature, the technology has been described as multivesicular

liposomes (MVL). Both terms will be used synonymously in this article.

DepoFoam or MVL are distinguished from liposomes such as unilamellar vesicles (ULV) and

multilamellar vesicles (MLV) by the characteristic structure and composition of MVL (Fig. 1).

Fig. 1. Comparison of the internal structure of a unilamellar liposome, a multilamellar liposome and a DepoFoam1

particle (multivesicular liposome, MVL) [28].

4. Mechanism of release ................................................................................................ ............................................. 402

5. Sustained release pharmacokinetics ....................................................................................................................... 405

References ................................................................................................................................................................... 405

1 Abelcet is the registered trademark of Elan (previously Liposome Technology Inc.). Ambisome and DaunoXome

are registered trademarks of Gilead (previously NeXtar), Amphotec and DOXIL are registered trademarks of ALZA

Inc. (previously Sequus Pharmaceuticals).

S. Mantripragada / Progress in Lipid Research 41 (2002) 392406 393


3/15

While ULV are liposomes with a single bilayer surrounding an aqueous compartment and MLV

are liposomes with concentric lipid bilayers, DepoFoam particles (or MVL) are composed of

non-concentric multiple lipid layers. It has been suggested that the non-concentric nature of the

arrangement of lipid layers confers an increased level of stability and longer duration of drugrelease [4]. This is because only breaches in the outermost membranes of an MVL result in release

of encapsulated drug to the external medium, and release of drug from the internal vesicles results

in a redistribution of drug inside the particle without drug release from the particle. The inter-

connected network of the multivesiculated structure also ensures that the vesicles can rearrange

themselves internally without release of drug by internal fusion and division. These events are

characteristic of and are possible with MVL system due to the non-concentric, close-packed nat-

ure of the particle, but not with the concentric multivesicular liposomes, the single-vesicle based

liposomes, or with the non-concentric but not closely packed plurilamellar liposomes. A detailed

structural characterization of MVL is discussed later.

1.1. Structure

One of the earlier published reports on the internal structure of MVL was based on light

microscopy and thin-section transmission electron microscopy [5]. Morphologically, MVL were

described as spheroids with granular internal structures under the light microscope. The details of

the membrane were seen best with transmission electron microscopy, which revealed that a

bilayer formed the outermost membrane and the internal space was divided into numerous com-

partments by bilayer septa. It was hypothesized that the essential component, neutral oil, became

part of corners or edges where membranes meet each other, thus stabilizing membrane bound-

aries analogous to planar black lipid membranes that also require a neutral lipid. Some of the

putative corners were seen in the electron micrographs as osmiophilic buttons which wereconsidered to be collections of triglycerides. In this respect the MVL differ from all other types of

liposomes.

A detailed quantitative study using freeze-fracture electron microscopy showed that the struc-

ture of MVL is governed by general topological constraints in analogy to gas-liquid foams, sim-

ple liquids, and metallic glasses [6]. Freeze-fracture images of MVL provided direct visual

confirmation that the compartment contacts are tetrahedrally coordinated, as dictated by rules

set down by Plateau in the last century (Fig. 2). From the experimentally measured distribution of

polyhedral facets of the MVL, it has been shown that the distribution of compartment shapes is

in near perfect agreement with theoretical predictions and computer simulations of random close

packing of polytetrahedra. This polyhedral random close packing of the internal vesicles is adirect analog of the way bubbles are packed in a gasliquid foam.

The close packing of vesicles formed by lipids and the encapsulated aqueous phase are also

apparent in fluorescent micrographs [7]. In this study, multivesicular liposomes were labeled with

a lipid probe, rhodamine-DHPE, and an aqueous probe, Bodipy disulfonate. As seen in Fig. 3,

while rhodamine-DHPE revealed the lipid matrix surrounding aqueous chambers, the Bodipy

disulfonate showed discrete non-concentric aqueous compartments inside the multivesicular

liposome.

At the molecular level, the distribution of phospholipids and triglycerides in MVL was deter-

mined using laser scanning confocal microscopy and 13C NMR [8]. Confocal microscopy with

394 S. Mantripragada / Progress in Lipid Research 41 (2002) 392406


4/15

two phospholipid fluorescent probes, Rhodamine-DHPE and NBD-PG, and a triglyceride fluor-

escent probe, Bodipy-triglyceride, was used to visualize the distribution of the lipid components

in MVL. The micrographs revealed a uniform distribution of the two phospholipid probes in the

plane of the membrane, whereas the triglyceride probe accumulated at discrete locations. In theNMR spectra of MVL, components attributable to triolein in a liquid-like phase were observed,

Fig. 3. Confocal micrographs of DepoFoam particles recorded with a red fluorescent dye (Rhodamine DHPE) labeling

the lipids, a green fluorescent dye (Bodipy disulfonate) labeling the aqueous phase. In the merged image, the distribu-

tion of both the lipids and the encapsulated aqueous phases is seen [7]. The bar indicates 10 mm.

Fig. 2. Freeze fracture electron micrograph of a multivesicular liposome showing random close packing of the internal

chambers. Examples of faceted structures surrounding the internal chambers that are closely packed and tetrahedrally

coordinated are outlined and identified [6].



5/15

and the intensity of these components accounted for the triolein present in the sample. The NMR

and microscopy results are consistent with a structural model for MVL in which triolein acts as a

hydrophobic space filler at bilayer intersection points and stabilizes these junctions, and is also

present as oil droplets dispersed in the encapsulated aqueous compartments (Fig. 4).In a 31P NMR study, temperature dependence of the spectra was monitored [9]. At 15 C, The

31P NMR spectrum was a partially averaged anisotropic powder pattern typically seen for bilay-

ers with a low degree of curvature. When the temperature rose to 25 C, an isotropic spectral

component appeared. The intensity of the isotropic component relative to that of the anisotropic

powder pattern increased as the temperature was raised to 85 C. The temperature dependence

was reversible in that upon cooling to 15 C, only the powder pattern was observed. Interestingly,

light scattering and microscopy experiments ruled out the possibility that the isotropic compo-

nent was due to formation of small vesicles. A cubic phase is probably not involved since the

Fig. 4. Schematic illustrating locations of the triglycerides in MVL based on NMR and confocal microscopy [8].



6/15


7/15

aqueous component. The solvent spherules contain multiple aqueous droplets with the substance

to be encapsulated dissolved in them. The organic solvent is removed from the spherules, gen-

erally by evaporation, by reduced pressure or by passing a stream of gas over or through the

suspension. When the solvent is completely removed, the spherules become MVL.Various types of lipids can be used to make MVL, and the only requirements regarding lipids

are that at least one amphipathic lipid (e.g. phospholipids) and one neutral lipid (e.g. triglyceride)

be included in the lipid component. When the neutral lipid is omitted, conventional multilamellar

vesicles or unilamellar vesicles are formed instead of multivesicular liposomes [10]. It is also cri-

tical that the double emulsification process be employed in order to form the multivesiculated

structure. When other well-known methods for the preparation of liposomes are employed, even

when the required mixture of phospholipids and triglycerides is used, MLV and ULV are formed

instead of multivesicular liposomes.

Not only is a triglyceride required for the formation of MVL, but the concentration of trigly-

ceride also has a profound eff

ect on capture volume and encapsulation effi

ciency (Fig. 6). In amixture with phosphatidylcholine, cardiolipin and cholesterol (4:5:1:4.5 mole ratio) maximal

capture volume and encapsulation efficiency are obtained in the triolein mole fraction range of

0.010.08 [5]. At lower triolein mole fractions the capture efficiency is reduced markedly.

Fig. 6. Effect of mole fraction of triolein with respect to other lipids in MVL on capture volume (ml/mg) and encap-

sulation (%). In addition to triolein, the lipid combination consisted of phosphatidylcholine, cardiolipin and choles-

terol in the relative proportions of 4.5:1: 4.5 mmol, respectively. Data are from [5].



8/15

In order to produce sterile commercial scale batches of a DepoFoam product conforming to

regulatory requirements, aseptic processing techniques are employed [1115]. The productionmethod is treated as a set of four sequential unit operations namely, first emulsion, second

emulsion, solvent extraction, and microfiltration. Table 1 lists the independent variables to be

optimized for each unit operation, along with a dependent variable utilized to judge the quality of

material produced at the end of the unit operation.

3. Methods for controlled release

Both the lipid components and the composition of the encapsulated aqueous phase can be used

to modulate the rate of sustained release from MVL.The release rate of the biologically active compound can be modified by utilizing in the pre-

paration of MVL, a neutral lipid component (typically a triglycerides) that provides the desired

rate of release in the type of fluid in which the MVL are to be used (Fig. 7). It has been found that

long chain triglycerides result in slower release rates from the MVL formulations than short chain

triglycerides do [16], presumably due to a stabilizing effect on the structure of the particle by

increased chainlength. In mixtures, the rate of release of the biologically active compound decreases

in proportion with the increase in the ratio of the slow release neutral lipid to the fast release neutral

lipid [16]. The slow release neutral lipid is selected from triglycerides having mono-unsaturated fatty

acid ester moieties containing about 1418 carbons in the acyl chain and generally having a molecular

Table 1

Individual and sequential unit operations during manufacturing scale-up

Unit operation Independent variables Dependent variables

First emulsion Mixing speed, mixing time, energy input

per unit volume, temperature

Viscosity, conductivity, particle size

Second emulsion Mixing speed, mixing time, impeller

diameter, impeller design, temperature,

volume of second aqueous phase

Particle size, particle size distribution

Solvent extraction Gas flow rate profile, degree of foaming,

temperature

Rate of solvent removal, extent of

solvent removal, step yield

Microfiltration Process flow rates, recirculation mass flow,

volume of buffer exchange

Processing time, buffer flow rate, step yield

Overall process Comparison to pilot scaleParticle size,

loading, overall yield, product stability,

drug release (in vitro and in vivo) profile

Independent variables optimized for each unit operation and the dependent variables used to determine completion of

optimization are also listed [11].



9/15

weight about 725885, and those with saturated fatty acid ester moieties containing about 10

12 carbons in the acyl chain and generally having a molecular weight about 554639. Choles-

terol esters and esters of propylene glycol can also be used. While triolein, tripalmitolein, tri-myristolein, trilaurin and tricaprin fall into this category, triolein or tripalmitolein are most

preferred. The neutral lipid inducing fast release is selected from triglycerides having saturated

fatty acid ester moieties containing from about 6 to 8 carbons in the acyl chain and having a

molecular weight from about 387 to 471. Tricaprylin, and mixtures of tricaprylin and tricaproin,

or mixed chain C6 to C8 triglycerides are most preferred. However, the use of neutral lipids with

less than six carbons (e.g. tricaproin) in the acyl chain results in a rapid release of the encapsu-

lated compound. By adjusting the slow release to fast release lipid ratio, the rate of release could

be adjusted for a number of molecules such as G-CSF, GM-CSF, recombinant human insulin-

like growth factor-1 (IGF-1), recombinant human insulin, morphine, cytosine arabinoside, a 15-

mer interleukin-6 antisense oligonucleotide, Escherichia coli plasmid PBR 322, tetracaine, andsucrose.

The osmolarity of the aqueous phase containing the drug that is mixed with the immiscible

solvent phase containing lipids is an important determinant of in vivo rates of release [17]. The

rate of release of the active substance into the surrounding in vivo environment can be decreased

by increasing osmolarity of this solution (Table 2). The decay half-life of the amount of cytar-

abine in the intraperitoneal cavity of mice was 0.64 h for an MVL formulation prepared with an

aqueous solution containing 82 mM cytarabine. The half-life was 13.6 h for an MVL preparation

made with 246 mM cytarabine solution. If the mechanism of release in vivo is exclusively classical

diffusion, one would expect that the rate of release is faster for the formulation with the greater

Fig. 7. Effect of the composition and chainlength of triglycerides on in vivo pharmacokinetics [16]. Pharmacokinetics

of morphine MVL formulations manufactured with different mole ratios of triolein to tricaprylin and injected into the

epidural space of Beagle dogs. Morphine released from the MVL was determined by measuring the level of morphine

in the adjacent, dura membrane-separated, cerebrospinal fluid. Results from an injection of 5 mg unencapsulated

morphine (sulfate) in saline (^); 40 mg of morphine in MVL with a triolein:tricaprylin mole ratio of 10:0 (!), 20 mg of

morphine in MVL with a triolein:tricaprylin mole ratio of 1:4 (*), 1:9 (&), and 0:10 ().



10/15

concentration gradient of drug (246 mM formulation) between the inside of the particle and the

peritoneal fluid than for the 82 mM formulation with the a lower gradient. The fact that theresults are in the opposite direction indicates that the in vivo release is dominated by mechanisms

other than simple diffusion.

Use of different acids in the first aqueous solution has a profound effect on release rates [18].

The half-life for in vitro release into human plasma from MVL formulations ranged from 1.6 to

37.2 h depending on the acid added to a solution of cytarabine at a constant concentration

(Table 3). In another study, it was found that the addition of a polyhydroxy organic acid (eg.,

glucuronic acid), or triprotic mineral acids (e.g. phosphoric acid) provides a synergistic effect with

respect to loading of bupivacaine [19]. With an MVL preparation of bupivacaine prepared using

this method, a half-life of 12 h was reported for bupivacaine at the intracutaneous injection site in

Table 3

Release in vitro of MVL-encapsulated drug (cytosine arabinoside) into human plasma at 37 C from various Depo-

Foam formulationa

Acid Half life in days

Perchloric 37.28.0

Nitric 54.55.7Phosphoric 6.50.2

Formic 5.60.2

Trichloroacetic 5.50.6

Acetic 4.80.5

Trifluoroacetic 3.40.4

Sulfuric 1.60.5

a Each formulation was prepared with a constant concentration of cytarabine (20 mg/mL), and a constant con-

centration (136 mM) of one of the acids listed in the table [18].

Table 2

Concentration of cytarabine in the pellet fractions of the peritoneal fluid, and the total amount of cytarabine in the

peritoneal cavity, at different times subsequent to intraperitoneal injection to mice of MVL formulations prepared

using a solution containing either 82 mM cytarabine or 246 mM cytarabine

a

Hours after intraperitoneal

injection

Concentration in pellet fraction, mg/ml Total amount (mg)

82 mM

formulation

246 mM

formulation

82 mM

formulation

246 mM

formulation

0 9380 9685 2372 2791

0.5 9925371 68961,083 110867 120248

4 11151,108 13,360761 15014 1493132

15 1015922 11,493 7658 790419

64 ND 1493132 ND 388191

108 ND 634518 ND 5834

t1/2

(r2) 1.7 (0.974) 29.6 (0.904) 0.64 (0.989) 13.6 (0.892)

ND, not determined; t1/2, decay half-life in hours.a A group size of three was used [17]. The pellet fraction contains closely packed MVL particles, and analysis of

pellet allows one to determine the concentration of drug inside the particles.



11/15

guinea pigs. In comparison, an unencapsulated free bupivacaine hydrochloride solution gave a

half-life of 1.3 h. The half-life values decrease roughly as both the charge and the size of the

counterion increase, suggesting that permeation of the salt complex is an important determinant

of drug release.

Water-soluble compounds such as methotrexate can interact with cyclodextrins to form an

inclusion complex. Encapsulation of the inclusion complex into MVL results in a release rate for

the drug that is slower than that from an MVL with just the drug encapsulated without formation

of the cyclodextrin inclusion complex [20]. The apolar cavity of the cyclodextrin sequesters the

compound sufficiently to slow the rate of release from MVL. The periphery of the inclusion

complex is hydrophilic with the result that the inclusion complex forms a solution in aqueous

media. Upon intrathecal injection in rats of 100 mg unencapsulated methotrexate, the amount ofdrug in the cerebrospinal fluid decayed with a half-life of 0.03 days. For an MVL preparation

with a cyclodextrin inclusion complex of methotrexate encapsulated, the corresponding half-life

increased to 9 days (Table 4). The areas under the curve (AUC) are comparable for the MVL

formulation and the unencapsulated drug suggesting that the relative bioavailability of the drug is

not altered by encapsulation.

4. Mechanism of release

The evolution of the structure of MVL with time as determined by freeze-fracture electronmicroscopy and in vitro release of encapsulated drug was followed in both human serum and

artificial cerebrospinal fluid [21]. Over a period of 9 days, the internal compartments in the MVL

grew in size and the average number of compartments per MVL decreased as cytarabine was

released, suggesting that internal coalescence plays a role in drug release (Fig. 8). The overall

MVL size decreased during aging, and some particles adopted irregular shapes. However, a sig-

nificant fraction of MVL retained their original multivesicular structure even after near-complete

release of cytarabine. These results suggested that permeation of drug through the vesicle mem-

branes is an important determinant of in vitro drug release. While cytarabine and most other

molecules studied with MVL are water-soluble compounds with low octanolwater partition

Table 4

Pharmacokinetic (PK) parameters for a subcutaneous injection of either unencapsulated methotrexate (MTX) or a

DepoFoam (MVL)-encapsulated cyclodextrin (CD)-complex of methotrexate (MVLCDMTX)a

MTX MVLCDMTX

Injection site

Amount t1/2 (h) 0.16 50.4

Plasma

CmaxS.D. (mM) 17.45.2 0.1380.061

Concentration t1/2 (h) 0.53 109

AUC (mM h) 17.3 24.5

a PK parameters obtained by measurements both at the subcutaneous injection site and in plasma are given in the

table [20].



12/15

coefficients, it is likely that membrane partitioning will play a critical role for molecules with highpartition coefficients.

Both during in vitro incubation in human plasma and in vivo in a subcutaneous hollow fiber

implant study in rats, lipid reorganization leading to coalescence of internal chambers followed

by formation of blebs at the surface of excess lipid were observed [22]. The internal chamber size

was determined by fluorescence confocal microscopy. This study also suggested that the hydro-

carbon chain length of the triglyceride and the concentration of the shorter versus longer chain

triglycerides determine the rate at which such internal membrane reorganization and coalescence

take place.

Cytarabine release over a 2-week period at 37 C was found to be dependent on the medium of

incubation [23,24]. The media investigated in this study included human plasma, artificial cere-brospinal fluid, simulated gastric fluid, phosphate buffers at pH 6 and 7.4, phthalate buffers at pH

3, 4 and 5, and hydrochloric acid at pH 2. The release rate in human plasma was much faster than

in the other low-protein media or buffers of similar pH. In low pH media (simulated gastric fluid

and pH 2 solution), large aggregates were formed as determined by particle size measurements.

Incubation at pH 3 had an intermediate effect on aggregation. Over the period of 2 weeks, par-

ticle size remained fairly constant for pH 47.4 buffers and for ACSF, while in plasma particle

size increased slightly. Particle concentration showed time-dependent behavior similar to that of

drug release for all media of pH 6 and above. For the low pH hypotonic media, drug release did

not correlate with particle concentration.

Fig. 8. Coalescence of internal chambers within a multivesicular liposome during incubation in human serum at 37 C

(J.A. Zasadzinski, personal communication). Multiple freeze fracture images were recorded on each day on samples

withdrawn from incubation in human plasma at 37 C. The number of internal chambers in a given size range were

counted on for a total count of about a thousand chambers per sample. The normalized size distributions are plotted

against the diameter of the internal chamber.



13/15

The in vitro drug release, particle size and particle concentration data are consistent with the

overall mechanism of release composed of at least three components namely, diffusion, erosion

and attrition [24]. For the diffusion component, particle number (measured by hemocytometry)remains constant but the amount of drug retained within the MVL particles decreases over time.

Particle size remains essentially constant, except when the particles act as osmometers sensing the

loss of solute. For the erosion component, both particle concentration and internal drug con-

centration remain constant while particle size decreases. When the attrition part of the mechan-

ism is operative, particle concentration decreases while internal drug concentration and size

remain constant.

In an in vivo study, male mice were injected subcutaneously with amikacin encapsulated in

DepoFoam particles prepared with tritium labeled cholesterol [25]. At time points over 21 days,

the level of tritium was determined for the site of injection, plasma, several organs involved with

cholesterol processing or storage, and the residual carcass. At day 7, a decrease in radioactivitylevels was observed at the site of injection (Fig. 9). Concomitantly, an increase in tritium levels

was detected at day 7 in the plasma, organs, and residual carcass. After 21 days, 20% of the

initial dose remained at the site of injection, 20% of the initial dose had accumulated in the resi-

dual carcass, and detectable levels of radioactivity were present in the plasma and all organs.

Cholesterol is known to move spontaneously between membranes faster than phospholipids do

[26]. As a result, the amount of cholesterol remaining at the injection site may not be an indictor

of the number of DepoFoam particles remaining at the injection site. However, the fact that sig-

nificant residual cholesterol is detected at the injection site after 21 days suggests that the Depo-

Foam particles do remain at the site at least for 21 days.

Fig. 9. Biodistribution of tritiated cholesterol in MVL from the subcutaneous injection site into surrounding tissues

[25]. Remaining radioactivity at the injection site (^) and the carcass (&) are shown.



14/15

5. Sustained release pharmacokinetics

Pharmacokinetic data from DepoFoam formulations of a number of different drugs have been

reviewed extensively elsewhere [7,27]. These studies cover a wide variety of routes of injection such as

intrathecal, intraperitoneal, subcutaneous, intramuscular, epidural, subconjuctival and intravitreal

routes. The classes of molecules for which sustained release pharmacokinetics with DepoFoam

formulations have been demonstrated include antineoplastic agents (cytarabine, methotrexate, leu-

prolide), antibiotics (amikacin, gentamicin), analgesics and anesthetics (bupivacaine, morphine,

enkephalin), cytokines (interferon, IGF-1, IL-2, G-CSF, GM-CSF), DNA and oligonucleotides.

In general, single bolus injections of unencapsulated drugs result in plasma or serum elimina-

tion half-lives ranging from 0.13 h to 11 h (Table 5). Depending on the drug, dose administered

and the route of injection, single bolus injections of the corresponding DepoFoam formulationsincrease the elimination half-lives by a factor of 6600. The longest reported half-life is 156 h for

DepoFoam-encapsulated cytarabine injected intrathecally in a monkey model.

References

[1] Gabizon A, Barenholz Y. Liposomal anthracyclinesfrom basics to clinical approval of PEGylated liposomal

doxorubicin. In: JanoffAS, editor. Liposomes: rational design. New York: Marcel Dekker; 1999. pp. 34362.

[2] Sankaram MB. Commercial sustained-release injectable formulations by encapsulation. In: Senior J and

Radomsky M, editors. Sustained-release injectable products. Denver, CO: Interpharm Press; 2000. pp. 2539.

Table 5

Comparison of elimination half-life values obtained for a single bolus injection of DepoFoam formulations with those

obtained for a single bolus injection of unencapsulated drugsa

Drug Species Elimination half-life, t1/2 (h) Route of administration Possible clinical use

DepoFoam Unencapsulated

Cytarabine Monkey 156 0.74 Intrathecal Cancer

Cytarabine Mouse 21 0.26 Intraperitoneal Cancer

Cytarabine Rat 148 2.7 Intrathecal Cancer

Cytarabine Mouse 96 0.16 Subcutaneous Cancer

Cytarabine Rabbit 52.5 0.2 Subconjuctival Cancer

Methotrexate Rat 96 7.2 Intrathecal Cancer

Methotrexate Mouse 50.4 0.16 Subcutaneous Cancer

Methotrexate Mouse 45.6 0.54 Intraperitoneal Cancer

Morphine Rat 82 2.6 Epidural Pain Management

IGF-1 Rat 26 4 Subcutaneous Growth FactorInterferon a-2b Mouse 20 1.5 Intraperitoneal Viral Infections, Cancer

Bleomycin Mouse 31.8 0.13 Subcutaneous Antibiotic

2030Deoxycytidine Rat 23 1.1 Intraventricular Viral Infections

5-FUMP Rabbit 124 4.5 Intravitreal Viral Infections

a For intracavitary delivery (intrathecal, intraventricular, intravitreal and epidural), the pharmacokinetic profile shows

an initial distribution and a later elimination phase. Only elimination half-life values are reported in the table.t1/2 Values

were calculated using the concentration of drug versus time profile [7]. All formulations contained the phospholipids dio-

leoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol and cholesterol. They also contained triloein, except the IGF-1

formulation which was prepared with tripalmitolein. The typical amounts of the lipids are given in [5,6].



15/15

[3] Chiron Corporation. Physicians Desk Reference 2000;54:9358.

[4] New RRC. Influence of liposome characteristics on their properties and fate. In: Philippot JR and Schuber F,

editors. Liposomes as tools in basic research and industry. Boca Raton: CRC Press; 1995. pp. 320.

[5] Kim S, Turker MS, Chi EY, Sela S, Martin GM. Biochim Biophys Acta 1983;728:33948.[6] Spector MS, Zasadzinski JA, Sankaram MB. Langmuir 1996;12:47048.

[7] Mantripragada S. Drug Delivery Systems and Sciences 2001;1:1316.

[8] Ellena JF, Le M, Cafiso D, Solis RM, Langston M, Sankaram MB. Drug Delivery 1999;6:97106.

[9] Ellena JF, Solis RM, Cafiso D, Sankaram MB. Biophysical Journal 1998;74:A372.

[10] Schneider M. Process for the preparation of liposomes in aqueous solution. US Patent No. 4,224,179; 1980.

[11] Pepper C, Patel M, Hartounian H. Pharmaceutical Engineering 1999;19:818.

[12] Pepper C, Patel M, Hartounian H. BioPharm 1999;12:2634.




[16] Willis RC. Method for utilizing neutral lipids to modify in vivo release from multivesicular liposomes. US Patent

No. 5,891,467; 1999.

[17] Sankaram MB, Kim S. Preparation of multivesicular liposomes for controlled release of encapsulated biologicallyactive substances. US Patent No. 5,993,850; 1999.

[18] Sankaram MB, Kim S. Multivesicular liposomes with controlled release of encapsulated biologically active sub-

stances. US Patent No. 5,766,627; 1998.

[19] Kim S, Kim T, Murdandi S. Sustained-release liposomal anesthetic compositions. US Patent No. 6,045,824; 2000.

[20] Kim S. Cyclodextrin liposomes encapsulating pharmacologic compounds and methods for their use. US Patent

No. 5,759,573; 1998.

[21] Keller S, Strahler D, Spector M, Walker S, Kennedy M, Zasadzinski JA. Biophysical Journal 1997;72:A400.

[22] Willis RC, Gai W, McAllister DL, Samaniego AC. Proceed Intl Symp Control Rel Bioact Mater 1998;25:3901.

[23] Longenecker JP, Willis RC, Thrift R, Sankaram MB. Proceed Intl Symp Control Rel Bioact Mater 1997;24:2067.

[24] Thrift R, Solis RM, Lewcock K, Sankaram MB. Proceed Intl Symp Control Rel Bioact Mater 1998;25:42930.

[25] Brownson EA, Langston M, Tsai AG, Gillespie T, Davis TP, Intaglietta M. Proceed Intl Symp Control Rel

Bioact Mater 1998;25:423.[26] Bar LK, Barenholz Y, Thompson TE. Biochemistry 1986;25:67015.

[27] Mantripragada S, Howell SB. Sustained release drug delivery with DepoFoam. In: Brown D, editor. Drug delivery

systems for cancer treatment. New York: Humana Press; 2001 (in press).

[28] Sankaram MB, Kim S. Multivesicular liposomes with controlled release of encapsulated biologically active sub-

stances. US Patent No. 5,766,627; 1998.


Depot Formulation5

Documents

Transcript of Depot Formulation5