improving drug delivery by use of lipid self-assembly par ticle

7/30/2019 Improving Drug Delivery by Use of Lipid Self-Assembly Par Ticle

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Professor Fredrik Tiberg was

appointed President and CEO of

Camurus in January 2003. He is

also Professor of Surface and

Colloid Chemistry at Lund

University, Sweden. During 2001

and 2002, he was Visiting Professor

at Oxford University and Special

Supernumerary Fellow of University

College. Prior to his current

position as President and

CEO of Camurus, Professor Tiberg

held a position as Vice President,

Head of R&D at Camurus. He was

appointed Associate Professor inPhysical Chemistry in 1998 and

Professor in 1999. In 1996 he

became Section Manager at the

Institute for Surface Chemistry,

Stockholm, Sweden. In these

professional roles, Professor Tiberg

has worked as consultant, scientific

advisor, and project coordinator,

serving a number of companies

from small to multinational

concerns. During the course of his

distinguished academic career,

Professor Tiberg has published more

than 80 original scientific papers

and co-authored several books. In

1994 he received his PhD in

Physical Chemistry from

Lund University.

a report by

P r o f e s s o r F r e d r i k T i b e r g

Professor of Surface and Colloid Chemistry, Lund University

I n t r odu c t i o n

Lipid-based drug delivery systems (DDS) can play a

direct role in improving efficacy and drug safety,

whereby new and improved therapies are possible.

This has stimulated the creative design and study of

lipid-based carriers for delivery through differentportals of the body. Colloidal-sized lipid particles in

aqueous media, and their pre-concentrated dosage

forms, have found important applications in a range

of drug products, featuring all routes of

administration. Lipid self-assembly structures even

find use as matrices for injectable depot products.

When dissolved in aqueous media, lipids self-

assemble to form a wide range of mesophase

structures (Figure 1). The complex architectures can

be advantageously utilised to facilitate solubilisation,

stabilisation, and delivery of different drugsubstances. Well-known self-assembly structures

creatively utilised in pharmaceutical products include

Sandimmun Neoral (microemulsion, Novartis),

Diprivan (emulsion, AstraZeneca), and Doxil

(Stealth liposome, ALZA).

More recently, lipid-based, self-assembled liquid

crystalline (LC) structures of cubic and hexagonal

phases, and their corresponding nanoparticles

(Cubosome and Hexosome), have emerged as

potential carriers for several applications. The broad

solubilisation spectrum together with high drugpayloads, as well as the ability to protect sensitive

substances like peptides and proteins, and facilitate

absorption, make these LC systems interesting

alternatives to the more commonly used micelle,

microemulsion, emulsion and liposome systems.

Similar to microemulsions, emulsion and liposomes,

they can be designed to self-disperse into colloidal

particles. This property is essential in many

applications where water-free liquid or powder pre-

concentrates are the desired dosage forms.

Lipids are ubiquitously distributed and playfundamental roles in the architecture and

functionality of all living cells. Human health is

dependent on the regular ingestion of various lipids

because of their role in maintaining normal cellular,

physiological and developmental function. Our

natural delivery system operates via synergetic

interplay between lipids and various enzymes. A

wide variety of lipid self-assembly structures with

specific structural and functional attributes can be

prepared by exploiting the self-assembly properties

unique to different lipids. Here, we briefly introducelipid-based systems used in pharmaceutical products

and development.

As noted above, lipid-based DDS represent a diverse

group of formulations, each having different

structural and functional characteristics which can be

modified by adjusting the contents of different lipid

excipients and other additives. The spectrum of

varying properties seems unlimited, but is, in

practice, restricted by cost, convenience, safety and

regulatory demands. The introduction of new

excipient combinations and DDS will most likelystimulate the use of lipid-based DDS and lead to new

and improved therapies in the future. Many drugs on

the market, and in different development stages, have

non-optimal properties that potentially could be

improved by a suitable delivery system (see Table 1).

Here, we present different lipid-based DDS, illustrating

their principal uses and potential future applications.

Mi c e l l e s , M i c r o emu l s i o n s , a nd

Emu l s i o n s

These aggregates are the simplest self-assembly

structures of lipids and surfactants with a widespread

use in pharmaceutical products. The issue most

frequently addressed by these systems is solubility. A

low solubility and associated sluggish dissolution

severely reduces the bioavailability of many water-

insoluble drugs. Ideally, a formulation should enable

uptake by keeping the drug in the dissolved state as a

solubilisate throughout its GIT-transit. Successful oral

lipid formulations on the market include Kaletra

(lopinavir and ritonavir, Abbott) and Fortovase

(saquinavir, Roche). Particularly efficient are self-emulsifying drug delivery systems, SEDDS. A

hallmark of SEDDS is emulsification to a fine

emulsion when released into the lumen, despite very

gentle agitation. From a physicochemical point of

Improv ing Drug De l i ve ry by use o f L ip id Se l f -a ssembly Part i c l e

S t ruc ture s Beyond L iposomes and Emuls ions

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Drug Delivery

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Improving Drug Del ivery by use of Lip id Se l f -as sembly Par t i c le S t ruc tures

view, the process is a phase inversion phenomenon,

and the composition of a SEDDS must mediate very

low interfacial tension between the oil and aqueous

phases. The product Sandimmun Neoral

(cyclosporin A, Novartis) uses this approach and is

now the gold standard for treatment against rejection

following organ transplant. In this respect it should be

emphasised that the SEDDS microemulsions typically

cannot be utilised for parenteral drug delivery because

of safety issues regarding the excipients. This is due to

the comparably high activity of the excipients

employed in SEDDS formulations. On the other

hand, micelles and o/w emulsions have traditionally

been used extensively in parenteral formulations,

using relatively mild surfactants or lipids, such as

polysorbates, cremophors, egg lecithin, and soybean

oil. Examples of drugs intended for the i.v. route,

utilising micelles and o/w emulsions as solubilisation

aids, include Taxol

(paclitaxel, Bristol-MyersSquibb), which takes advantage of cremophor

micelles, and Diprivan (propofol, AstraSeneca),

which is an o/w emulsion.

L i po somes

Liposomes have been studied as drug carriers since the

1970s, but it took about two decades to develop the

first successful product applications. The constantly

growing stream of liposome publications illustrates the

enormous research effort going into this field. Based

on present clinical applications of liposomes, the future

is regarded with optimism, although developments

have not yet lived up to earlier high expectations.

Liposomes represent dispersed, closed, bilayer

assemblies of the lamellar phase in excess water.

Biologically active molecules, such as proteins, canbe incorporated into bilayers or the aqueous interior

of the liposomes whereby primitive mimetics of

biological cells are created. More importantly in this

context, is that loading and encapsulation of drug

substances in the interior aqueous core, or in the

bilayer domain, is possible. Liposome characteristics

depend on manufacturing protocol and excipient

composition. They can be made in sizes ranging

from unilamellar vesicles with a size as small as 20nm

to multilamellar structures 10m in diameter.

Table 1: Drug Delivery Issues Addressed by

Lipid-based DDS

1. Low aqueous solubility

2. Storage andin vivo stabilities

3. Local irritancy

4. Poor absorption

5. Rapid clearance

6. Dose-limiting toxicities

7. Poor distribution to target organs

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Among common lipid drug-carrier structures, the

liposome structures are uniquely adjusted for

delivery of hydrophilic drugs. This is due to the

presence of an internal aqueous milieu encapsulated

by an outer impermeable bilayer structure, whichacts as a chemical, mechanical, and electrical barrier

against the ambient media. Due to low permeability

of protons and other cations, they can be prepared

with acidic internal pH, which facilitates active

loading of water-soluble drugs (weak bases), and

can be used to enhance drug stability. Mechanical

properties and permeability of bilayer structures are

determined by choice of components. Saturated

phospholipids tend to be rigid and relatively

impermeable, whereas unsaturated lipids are

relatively flexible and more permeable. Current

liposome drugs on the market, and in latedevelopment phase, are typically i.v. products

featuring water-soluble and/or highly toxic/tissue-

irritant active substances, like doxorubicin,

daunorubicin and vincristine, and lipid-soluble

amphotericin B. Benefits of i.v. liposome carriers

include controlling the drug activity and toxicity.

Inside the liposome the product is inactive.

Avoidance of extravasation decreases the

distribution volume and can increase the circulation

half-life. The plasma half-life can be further

enhanced by tethering stabilising polymer chains at

the liposome surface, e.g. PEG-lipids. Indirectly,this leads to changes in the biodistribution: to tissues

with enhanced vascular permeability to and,

thereby, to passive targeting of regions of

infection or inflammation, or to leaky blood vessels

characteristic of angiogenesis. Aside from passive

targeting, liposome structures can be equipped with

homing devices, such as surface-tethered

antibodies. Such liposomes become increasingly

complex. It is noteworthy that even simple things

are difficult in the pharmaceutical world, and that

such complex systems will require a substantial

upside in therapeutic index and market potential toeven be considered for drug development.

Utilisation of liposomes in administration routes

other than i.v. is, at present, limited because of the

complexity of liposome formulations and the

existence of better and simpler alternatives. There are

a number of liposomal DDS on the market,

however, that are intended for the s.c. or i.m. routes.

One example of a depot technology based onliposomes is the DepoFoam from SkyePharma.

Another current interesting clinical development

concerns transdermal liposome drug products. Such

systems are in clinical development, featuring actives,

e.g. Transfersomes with ketoprofen developed by

IDEA, claiming improved bioavailability.

Nanopa r t i c l e s o f N on - l ame l l a r

Ph a s e s Cub i c , H ex a gon a l

and S pon ge

As seen in Figure 1, lipids can self-assemble into

different non-lamellar geometries. From a drug

delivery perspective, these have attractive structural

attributes and functional properties. In analogy with

the liposomal dispersions, non-lamellar particles can

be produced in multiphase systems, comprising a

non-lamellar phase and excess water. This was first

observed in a study of fat digestion, where cubic-

phase particles were identified. It was later found that

similarly structured particles could be prepared by

dispersing glycerol monoleate (GMO) in water in the

presence of surfactant and polymeric stabilisers. Thefull potential of non-lamellar colloidal particles,

however, has not been realised in pharmaceutical

applications. As with liposomes, drug delivery

applications have been hampered due to the absence

of suitable manufacturing methods for preparing

structurally well-defined and stable dispersions, and

because of the fact that only a few known lipid

systems exhibit suitable phase behaviour. Recent

developments allow scientists to take advantage of

the true potential of non-lamellar phase structures in

drug delivery applications.

The main issues addressed by the non-lamellar LC

phases, and their corresponding nanoparticles, are

solubilisation, drug payload, and protection of

sensitive drugs in vivo against rapid degradation by


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Drug Delivery

Figure 1: Different Self-assembly Objects Formed by Lipids/surfactants in Aqueous Media

Oil in water

Reversed

micelles (L2)

Reversed

hexagonal (H11)Micelles (L1) Hexagonal (H1) Lamellar (L) Cubic (Q)

Mirror plane Water in oil

In this report, special emphasis is put on the water-in-oil-type of structures, such as the bicontinous cubic (Q) and the reversed hexagonal (HII) phas e.


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Improving Drug Del ivery by use of Lip id Se l f -as sembly Par t i c le S t ruc tures

endogenous enzymes. Examples of lipid-based

liquid crystalline nanoparticles (LCNP) are shown

in Figure 2. Especially noteworthy is the nano-

structured interior of the particles, featuring both

hydrophilic (aqueous) and lipophilic (lipid)

domains. In contrast to liposomes, which consist

mostly of water even for relatively small liposomeradii, the lipid content of typical LCNP is high

(normally ranging 5070wt%). Because of

coexisting hydrophilic and lipophilic domains, and

the enormous surface area possessed by these

structures, they have a broad spectrum of

applicability, comprising lipophilic and amphiphilic

bioactive agents, and peptide and protein drugs.

In this context it can be pointed out that normal o/w

emulsions are best adapted for strongly lipophilic

drugs that require an oil medium for optimal

solubilisation. Contrastingly, amphiphilic drugs, andin particular peptides and proteins, are often less

compatible with emulsion systems. Also, compared

with liposomes, drug payloads can be increased

considerably using a LCNP DDS. An example is

given in Figure 3, where loading capacity of

cyclosporine A into LCNP carriers (Cubosome and

Hexosome) is compared with that of liposome and

microemulsion formulations, respectively.

Important recent developments allow for the LCNP

to be formed, by self-dispersion or self-

emulsification, from a water-free formulationpreconcentrate similar to the SEDDS microemul-

sions. The Flexosome particles in Figure 2 are based

on a so-called sponge phase and can be produced

simply by gentle magnetic stirring. High drug-

payload characteristics of a broad spectrum of drugs,

together with in situ emulsification, imply that the

Flexosome system is ideal for oral applications

where self-emulsifying properties are desired for

convenience and optimal performance.

Early non-lamellar LCNP preparations featured

lipids that were not well-suited for parenteral drugdelivery, as exemplified by the unsaturated

monoglyceride (uMG) GMO. Together with

unreliable and scalable manufacturing schemes, the

scope of application of the LCNP has been limited.

Later improvements concerning both manufacturing

schemes and excipient base have now finally

facilitated the use of non-lamellar phases and

nanoparticles in parenteral drug delivery. Using

biodegradable and well-tolerated lipid excipients and

reproducible, reliable, and scalable manufacturing

schemes, the final obstacles for the use of non-

lamellar LCNP DDS in parenteral applications hasnow been overcome.

Other promising delivery routes of non-lamellar

LCNP are the nasal and transdermal routes. The

Eurocine L3 adjuvant is a sprayable nasal vaccine

based on a low viscous sponge phase. Composed of

endogenous and pharmaceutically accepted lipids, it

is approved for human use and a successful phase I

trial of nasal immunisation with diphtheria vaccine

has recently been performed.

Summary and F u tu r e

Ou t l o ok

Self-assembled LC structures provide a wide

spectrum of structural and functional features. It

appears that these attributes can be advantageously

utilised to fit virtually any drug delivery challenge,

making lipid-based DDS a successful approach.

Key challenges related to manufacturing, stability,

and reproducibility have been overcome, adding

new opportunities of optimising drug product

performance with regards to therapeutic index and

patient convenience and compliance. Currently,

non-lamellar LCNP are being implemented aspromising approaches in a number of late-stage

development products. A growing pipeline of

products utilising lipid-based LC and LCNP DDS

can be foreseen in the near future.


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Figure 2: Cryogenic Transmission Electron Microscopy (cryo-TEM) Images of

Liquid Crystal Nanoparticles (LCNP). From Left to Right: Cubosome,

Hexosome, and Flexoso me

Figure 3: Drug Loading Capacity of Cubosome (QS)

and Hexosome (HS) in Comparison with a

Liposome (LS) and a Microemulsion (ME)

Formulation. Cyclosporine A was used as a Model

Drug and the Drug Loading Capacity is given in

Weight of Drug per Excipient Weight

30

25

20

15

10

5

0QS1 QS2 HS1 LS ME

Carr

iercapacity

%

improving drug delivery by use of lipid self-assembly par ticle

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