Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02369594 2001-11-06
Lipid particles of various sizes are employed for the
controlled delivery of drugs. Hard gelatine capsules are
filled with medicament-loaded lipid pellets with a size of
approximately 0.10 - 2.0 mm, and the drug undergoes prolonged
release from the lipid pellets, (commercial product
Mucosolvan° [Mizller, R. H., Feste Lipidnanopartikel [Solid
lipid nanoparticles] (SLN), in Miiller, R. H., Hildebrand, G.
E. (eds.), Pharmazeutische Technologies Moderne Arzneiformen
(Pharmaceutical technology: modern dosage forms],
Wissenschaftliche Verlagsgesellschaft Stuttgart, 357 - 366,
1998]). Lipid microparticles can be used for various
application routes, from topical products (e. g. 0/W creams)
through oral medications to parenterals. An order of magnitude
smaller are solid lipid nanoparticles (SLN~), which have an
even wider range of use. Because of the fineness of the
particle size, ophthalmological use is for example also
possible.
Lipid particles can be employed in the form of a free-flowing
dispersion, i.e. the lipid particles are dispersed in an
aqueous phase (e. g. in isotonic glucose solution) or in a non-
aqueous phase (e.g. in PEG 600 or oil). when used as a
dispersion, the system must generally be free-flowing, i.e. of
low viscosity. The lipid concentration in the dispersions is
generally relatively low, in the range of approximately 1 -
10% (per cent by weight). This is sufficient for most
application purposes. If necessary, the lipid particle
concentration may also be readily increased to up to 20%
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(similar to 20% oil containing emulsions for parenteral
nutrition) .
The situation regarding the required lipid concentration is
different when incorporating lipid particles into traditional
dosage forms such as creams, oral medicinal forms such as
tablets, pellets or capsules, as well as in the case of
parenterals with a limited injection volume. Substantially
higher lipid concentrations are required here in order to
reduce the proportion of water in the dispersion, which must
be removed in order to produce the tablets, for example. This
is true, in particular, when large amounts of lipid need to be
incorporated into these medicinal forms, owing to the low
medicament-loading capacity of the particles.
The incorporation of highly concentrated lipid particles into
these medicinal forms is not difficult when relatively large
particles are involved (> 100 Vim). The lipids can be ground to
a coarse powder using a conventional mill. The particles thus
obtained at a size of 100 - 200 ~,m are admixed as a powder in
the production process of the dosage form.
The situation is more difficult with lipid microparticles and
lipid nanoparticles. For lipid microparticles in the range of
approximately 1 - 100 ~,m, highly energetic grinding is
necessary in order to achieve this fineness of the particle
size. The heat inevitably given off during the grinding
process can partially melt the lipid and cause clumping;
compensatory cooling is generally necessary. Fine powders,
especially in the case of a hydrophobic surface, are
susceptible to particle aggregation. In order to avoid this
problem, wet grinding is essential, optionally with the
addition of a surfactant. Highly fine lipid particles, i.e. in
the range of a few micrometres and in particular in the
nanometre range, cannot generally be produced by dry grinding.
For wet grinding, the coarse lipid powder is dispersed in a
liquid and is processed using an appropriate wet mill (e. g.
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colloid mill). Further possible modes of production include
high pressure homogenisation methods [Muller, R. H., Feste
Lipidnanopartikel (SLN), in Miiller, R. H., Hildebrand, G. E.
(eds.), Pharmazeutische Technologies Moderne Arzneiformen,
Wissenschaftliche Verlagsgesellschaft Stuttgart, 357 - 366,
1998] or alternatively precipitation [Morel, S., Ugazio, E.,
Cavalli, R., Gasco, M. R., Thymopentin in Solid Lipid
Nanoparticles, Int. J. Pharm., 259 - 261, 1996]. Highly fine
lipid particles can generally be incorporated into the
aforementioned dosage forms only in the form of a dispersion.
Highly concentrated lipid particle dispersions are essential
for the production of oral dosage forms and certain
parenterals. For the production of tablets, for instance, the
aqueous lipid particle dispersion is used as a granulating
liquid. The volumes of aqueous lipid particle dispersion to be
used for incorporating a particular amount of lipid particles
as granulating liquid must not be too high, since otherwise
too much water will need to be removed or granulation will no
longer be even possible. Similar considerations apply to the
use of aqueous lipid particle dispersions to make a paste of
the excipient mixture for pellet extrusion. Soft gelatine
capsules can be filled with non-aqueous lipid particle
dispersions. When the lipid has a given maximum drug-loading
capacity, the lipid particle dispersion must here also be
sufficiently concentrated in terms of lipid particles in order
not to exceed the maximum possible filling volume of the
capsule.
This will be explained with reference to an example. The
single dose of cyclosporin for adults is approximately 200 mg.
The lipid nanoparticles produced by using cyclosporin have a
maximum loading capacity of 20~, i.e. the lipid matrix
consists of 200 mg of cyclosporin and 800 mg of lipid [Miiller,
R. H., Runge, S. A., Ravelli, V., Pharmazeutische Cyclosporin-
formulierung mit verbesserten bio-pharmazeutischen
Eigenschaften, erhohter physikalischer Qualitat and
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Stabillitat sowie ein Verfahren zur Herstellung derselben
[Pharmaceutical cyclosporin formulation with improved
biopharmaceutical properties, higher physical quality and
stability and a method for the production thereof] , DE 198 19
273]. This single dose is to be administered in two tablets of
1 g each, i.e. 1 g of lipid/cyclosporin particles needs to be
made into a paste with 1 g of excipients, for tabletting in
the granulation process. At the current state of lipid
nanoparticle production technology, 1 g of cyclosporin-loaded
lipid nanoparticles is dispersed in 4 g of water (total volume
of the aqueous lipid nanoparticle dispersion: approximately 5
ml - 5 g). When mixing these 5 g with 1 g of tablet
excipients, it is hence necessary to remove 4 g of water; 2 g
of tablet mixture is obtained after the water is removed. It
is clear that granulation is not possible with such low-
concentration lipid nanoparticle dispersions (removal of 4 g
of water from 6 g of granule mixture). Lipid particle
dispersions with a lipid content of 50 - 70% are necessary.
Similar problems are encountered in the case of a) drugs
having on average a high single dose when incorporating drug-
loaded lipid particles into any traditional dosage forms and
b) drugs which, although they have a low single dose, are
nevertheless difficult to incorporate into lipid particles (_
low loading capacity).
The object of the invention was therefore to provide a
production method for the production of highly concentrated
lipid nanoparticle dispersions with a lipid content of from 30
to 95%, or a solids content (lipid + surfactant and/or
stabiliser) of from 30 to 95%.
The production of lipid microparticle dispersions in the lower
micrometre range is described in a number of patents, patent
applications and in the literature. The maximum lipid
concentrations used are, according to patent claims or
examples, in this case e.g. 3% [bomb, A., Lipospheres for
controlled delivery of substances, US-A-5,188,837, 1993], 30%
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[fiasco, M. R., Method for producing solid lipid microspheres
having a narrow size distribution, US-A-5,250,236, 1993] and
20% [Speiser, P., Lipidnanopellets als Tragersystem fur
Arzneimittel zur peroralen Anwendung [Lipid nanopellets as a
carrier system for peroral administration of medicaments],
European Patent EP 0 167 825, 1990]. For higher
concentrations, the formation of gels (fat in water) or
ointments (water dispersed in fat) is described. The maximum
amounts of fat used for the production of lipid nanoparticles
are 30% [Mizller, R. H., Lucks, J. S., Arzneistofftrager aus
festen Lipidteilchen [Medicament carriers consisting of solid
lipid particles], Solid Lipid Nanospheres (SLN), European
Patent EP 0 605 497, 1996]. Also in the case of lipid
nanoparticles, the formation of lipid gels (0,/w creams) is
described when higher amounts of lipid are used [Freitas, C.,
Muller, R. H., Effect of light and temperature on zeta
potential and physical stability in Solid Lipid Nanoparticle
(SLNTM) Dispersions, Int. J. Pharm. , 221 - 229, 1998] . For the
production of lipid nanoparticles by precipitation [fiasco, M.
R., Method for producing solid lipid microspheres having a
narrow size distribution, US-A-5,250,236, 1993], a hot lipid
microemulsion is added to a cold aqueous surfactant solution.
This precipitation step necessarily leads to very dilute lipid
nanoparticle dispersions. The maximum concentration obtainable
in the aqueous dispersion is, according to the patent, 0.5 -
3% [fiasco, M. R., Method for producing solid lipid
microspheres having a narrow size distribution, US-A-
5,250,236, 1993].
The object of the prior methods was to produce particle
dispersions which were homogeneous in terms of size.
Homogeneous particle dispersions are indeed emphasised in
those patents which carry out the particle production by means
of homogenisation methods. When dispersed in a homogenisation
medium, however, homogeneous particles are susceptible to
lining up in "pearl necklace" fashion and forming gels. The
classical example is the gel formation of uniformly sized
CA 02369594 2001-11-06
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Aerosil particles, which occurs in both aqueous and non-
aqueous media (e. g. oils) (Fig. 1). These pearl necklace-like
gels are described in the textbooks [List, P. H.,
Arzneiformlehre [Teachings on medicinal forms],
Wissenschaftliche Verlagsgesellschaft Stuttgart, p. 264,
1976]. Similar gel formation is, however, also described for
particles which are relatively polydisperse owing to their
production. The classical example of this are the bentonite
gels described in the textbooks [List, P. H., Arzneiformlehre,
Wissenschaftliche Verlagsgesellschaft Stuttgart, p. 264, 1976]
(Fig. 2) . The bonds within the gel framework of bentonite and
Aerosil are not covalent, but purely electrostatic and/or
hydrogen bridge bonds. Although there are no covalent bonds,
the gel frameworks are relatively stable; even low
concentrations lead to a highly viscous gel (e. g. 2% Aerosil
in Miglyol 812). In the case of lipid nanoparticles, it has
been found that they have a thin outer shell with a different
structure from the particle core [after Mizhlen, A., Schwarz,
C., Mehnert, W., Solid Lipid Nanoparticles (SLN) for
controlled drug delivery - Drug release and release mechanism,
Eur. J. Pharm. Biopharm. 45, 149, 1998, Lukowski, G., Werner,
U., Pflegel, P., Surface investigation and drug release of
drug-loaded solid lipid nanoparticles, Proc. 2nd World Meeting
APGI/APV, Paris, 573 - 574, 1998]. When particles come into
contact with one another, liquid crystalline a modification is
converted into solid i3 modification, lipid solid bridges are
formed and particle aggregates result (Fig. 3). As the
particle aggregation continues, a highly solid gel is formed
[Freitas, C., Mizller, R. H., Correlation between long-term
stability of solid lipid nanoparticles (SLNT"') and
crystallinity of the lipid phase, Eur. J. Pharm. Biopharm. 47,
125 - 132, 1999] . It has been found that this gelling and gel
formation process is commensurately stronger if the
concentration of lipid particles is higher. The lipid particle
concentrations investigated were relatively low at 0.1~ - 10%
[Freitas, C., Miiller, R. H., Correlation between long-term
stability of solid lipid nanoparticles (SLNT") and
CA 02369594 2001-11-06
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crystallinity of the lipid phase, Eur. J. Pharrn. Biopharm. 47,
125 - 132, 1999, Freitas, C., Lucks, J. S., Mizller, R. H.,
Effect of storage conditions on long-term stability of "Solid
Lipid Nanoparticles" (SLN) in aqueous dispersion, 18t World
Meeting APGI/APV, Budapest, 493 - 494, 1995]. During gel
formation, lipid particles additionally become quasi-"glued"
via lipid solid bridges.
In view of the above-described gel formation phenomena of
monodisperse and polydisperse particles, the mechanism of
solid bridge formation in the case of highly fine lipid
particles and the fast transition rate from a modification
into i3 modification, i.e. within minutes e.g. in the case of
hard fat [Sucker, H., Fuchs, P., Speiser, P., Pharmazeutische
Technologie [Pharmaceutical Technology], Georg Thieme Verlag
Stuttgart, 1978, Bauer, K. H., Fromming, K.-H., Fiihrer, C.,
Pharmazeutische Technologie [Pharmaceutical Technology], G.
Fischer Verlag Stuttgart, p. 276, 1997], the production of
highly concentrated lipid dispersions at a size of a few
micrometres and, in particular, nanometres seemed unfeasible.
Surprisingly, however, it has been found that a 40%
concentrated high pressure homogenised lipid dispersion
contained separate nanoparticles (Example 1). Even when the
lipid content is increased further to 50%, it was still
possible to obtain separate nanoparticles (Example 2). To
produce lipid particles in the upper nanometer range or lower
micrometre range, a rotor-stator (Ultra-Turrax, Janke &
Kunkel, Germany) was used as a dispersing system with lower
power density (Example 3). The production of lipid particle
dispersions of uniform particle size (monodisperse) with a
solid content significantly above 74% is physically
impossible. With the densest spherical packing, the solids
volume is 74% and that of the pores in between (the water
phase in the case of lipid particle dispersions) is 24%. In
order to enable denser packing, lipid particle dispersions of
non-uniform particle size were therefore deliberately
produced. To that end, contrary to conventional wisdom and
CA 02369594 2001-11-06
teaching, suboptimal dispersing conditions (low pressure) or
suboptimal dispersing devices (non-uniform power-density
distribution) were deliberately used (Example 4). The
production conditions and production devices used were
precisely the opposite of those which are recommended in the
literature for the production of lipid particle dispersions.
Non-uniform size allows denser packing for the same distance
between the particles, since smaller particles can fit into
the gaps between larger particles, whereas the particle
integrity is nevertheless surprisingly preserved.
The solids concentration of the lipid particle dispersions
described in this invention is in the range of from 30% up to
95%. As the solids content increases, the production
conditions need to become more suboptimal, i.e. the particle
dispersion produced needs to become more polydisperse. In the
upper concentration range, it is also necessary to add the
lipid phase thereto successively in several steps. The
stepwise added lipid fraction becomes finely dispersed in the
water phase in the presence of lipid nanoparticles already
present. After the dispersion and conversion into lipid
nanoparticles has been completed, a further lipid fraction is
added. For instance, when producing 100 g of an 80% lipid
particle dispersion, instead of directly adding 80 g of lipid
to 20 g of water, 20 g of lipid may be first introduced into
20 g of water (= 50% strength dispersion) and a further 10 g
of lipid may then be added in each of 6 further sub-steps.
Each step therefore involves the dispersion of 10 g of lipid
in 20 g of water and automatically, owing to the volume
proportions, the formation of an O/W system.
The lipid may be dispersed in the outer phase either in the
solid state (cold homogenisation) or in the liquid state (hot
homogenisation). In the case of cold homogenisation, the lipid
is dispersed in an aqueous surfactant solution (raw
dispersion) and then treated further using a suitable device.
In the case of hot homogenisation, the lipid is melted and
CA 02369594 2001-11-06
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poured into the outer phase, which is heated to the same
temperature, and dispersed therein (raw emulsion). The raw
emulsion obtained is then processed using a further dispersion
device. Depending on the desired degree of dispersion, the
concentration of the lipid phase and the aggregate state of
the lipid, the following may be used as dispersion systems:
high-pressure homogenisers of the piston-gap homogeniser type
(APV Gaulin systems, French Press), jet-stream homogenisers
(e. g. microfluidisers), rotor-stator systems (Ultra-Turrax,
Silverson homogenisers) and static blenders on the micro-scale
or macro-scale (e. g. Sulzer, Switzerland).
In particular in the case of dispersing highly concentrated
molten lipids (hot homogenisation), it has been assumed that
the typical biamphiphilic cream structures described in the
textbooks are formed [Bauer, K. H., Fromming, K.-H., Fuhrer,
C., Pharmazeutische Technologie, G. Fischer Verlag Stuttgart,
p. 276, 1997] (Fig. 4) . From such structures, it is no longer
possible to obtain particles such as e.g. nanoparticles. In
the present invention, however, integer particles were
surprisingly obtained even at a high lipid concentration.
Additives may be used to promote the formation of particles
while minimising particle aggregates. Such additives are
substances which shift the pH (e. g. increasing the zeta
potential, influencing the surfactant structure and degree of
dissociation) or deliberately increase the particle charge
(e. g. anti-flocculants such as sodium citrate). Such additives
can also increase the stability of the lipid particle
dispersion, e.g. by influencing the water structure (e. g.
electrolytes) or by effects on the stabilising surfactant
layer (e. g. glucose in the case of lecithin).
The lipid particles may be loaded with active agents. Examples
of active agents include drugs, cosmetic active agents,
agricultural pesticides, food additives, chemical substances
of various types (e. g. wood preservatives).
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The loading with active agents may be carried out in various
ways, individually or in combination. The active agent or
agents are dissolved, solubilised (e.g. using surfactants or
cyclodextrins) or dispersed in the lipid particles. Further
they can be adsorbed at the surface of the particles . Because
of their solid nature, it is also possible to incorporate
hydrophilic active agents into the lipid phase in the form of
an aqueous active-agent solution. This incorporation and the
subsequent dispersion of the lipid in the aqueous dispersion
medium results in a W/F/W system, i . a . water in fat in water .
Because of its solid aggregate state, the lipoid core in this
case encloses the aqueous drug solution better than is
possible with comparable multiple water in oil in water
(W/O/W) emulsions.
The lipid particles according to the invention may be produced
in the following way:
1. Dispersing the inner phase (the lipid or lipoid) in the
molten or softened state. The dispersion takes place above
room temperature and may be carried out using various
methods, for example the ones described below.
2. Dispersing the solid inner phase in the solid state. The
solid phase is for this purpose finely comminuted and
dispersed in water or in an aqueous medium.
The dispersed lipid core, which is solid at room temperature,
has been loaded beforehand with one or more active agents.
This may be done by dissolving or dispersing the active agent
in the lipid, or aadsorbing it on the surface, or dispersing
it in the lipid in the form of an aqueous solution or
simultaneously incorporating it using several of these
methods.
The incorporation of the active agent or agents may be carried
out using various methods. Examples include:
CA 02369594 2001-11-06
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1. Dissolving the active agent in the inner phase.
2. Dissolving the active agent in a solvent which is miscible
with the inner phase and adding this active-agent solution
to the inner phase. Optionally, the solvent may then be
partially or completely removed.
3. Dispersing the active agent in the inner phase (e.g. by
dispersing a solid or controlled precipitation).
4. Dissolving the active agent in the outer aqueous phase
(e. g. amphiphilic substances) and incorporating the active
agent into a surfactant film which stabilises the
particles, during production.
5. Adsorbing the active agent on the particle surface.
6. Dissolving the active agent in the lipid phase by means of
a solubiliser (e. g. a block copolymer or fatty acid
sorbate), and subsequently dispersing the lipid phase in
order to produce the raw dispersion. The active agent is
then present as a solid solution in the particles.
7. Incorporating aqueous active-agent solutions into the
lipid phase and subsequently dispersing the lipid phase in
order to produce the raw dispersion, so as to create a
W/F/W system which is similar to multiple emulsions.
Active agents e.g. from the following chemical compound
classes may be incorporated:
- hydroxylated hydrocarbons
- carbonyl compounds such as ketones (e. g. halopedol),
monosaccharides, disaccharides and amino-sugars
- carboxylic acids such as aliphatic carboxylic acids,
esters of aliphatic and aromatic carboxylic acids,
basically substituted esters of aliphatic and aromatic
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carboxylic acids (e. g. atropine, scopolamine), lactones
(e. g. erythromycin), amides and imides of aliphatic
carboxylic acids, amino acids, aliphatic aminocarboxylic
acids, peptides (e. g. cyclosporin), polypeptides, f3-lactam
derivatives, penicillins, cephalosporins, aromatic
carboxylic acids (e.g. acetylsalicylic acid), amides of
aromatic carboxylic acids, vinylogous carboxylic acids and
vinylogous carboxylates
- carbonic acid derivatives such as urethanes and
thiourethanes, urea and urea derivatives, guanidine
derivatives, hydantoins, barbiturate derivatives and
thiobarbiturate derivatives
- vitro compounds such as aromatic vitro compounds and
heteroaromatic vitro compounds
- amines such as aliphatic amines, aminoglycosides,
phenylalkylamines, ephedrine derivatives, aromatic amines
and derivatives, quaternary ammonium compounds
- sulphur compounds such as thiols and disulphanes
- sulphones, sulphonates and sulphonic acid amides
- polycarbocycles such as tetracyclines, steroids with an
aromatic A ring, steroids with an alpha, beta-unsaturated
carbonyl function in the A ring and an alpha ketol group
(or methylketo group) at C 17, steroids with a butenolide
ring at C 17, steroids with a pentadienolide ring at C 17
and secosteroids
- O-containing heterocycles such as chromane derivatives
(e. g. cromoglycic acid)
- N-containing heterocycles such as pyrazole derivatives
(e. g. propyphenazone, phenylbutazone)
- imidazole derivatives (e. g. histamine, pilocarpine),
pyridine derivatives (e. g. pyridoxine, nicotinic acid),
pyrimidine derivatives (e. g. trimethoprim), indole
derivatives (e. g. indomethacin), lysergic acid derivatives
(e. g. ergotamine), yohimbane derivatives, pyrrolidine
derivatives, purine derivatives (e. g. allopurinol),
xanthine derivatives, 8-hydroxyquinoline derivatives,
aminohydroxyalkylated quinolines, aminoquinolines,
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isoquinoline derivatives (e. g. morphine, codeine),
quinazoline derivatives, benzopyridazine derivatives,
pteridine derivatives (e. g. methotrexate), 1,4-
benzodiazepine derivatives, tricyclic N-containing
heterocycles, acridine derivatives (e.g. ethacridine) and
dibenzazepine derivatives (e. g. trimipramine)
- S-containing heterocycles such as thioxanthene derivatives
(e. g. chlorprothixene)
- N,O-containing and N,S-containing heterocycles such as
monocyclic N,O-containing heterocycles, monocyclic N,S-
containing heterocycles, thiadiazine derivatives, bicyclic
N,S-containing heterocycles, benzothiadiazine derivatives,
tricyclic N,S-containing heterocycles and phenothiadiazine
derivatives
- O,P,N-containing heterocycles (e. g. cyclophosphamide).
In particular, the following groups and substances may be
incorporated as medicaments, e.g. as a salt, ester, ether or
in the free form:
Analgesics/antirheumatics
BTM bases such as morphine, codeine, piritramide, fentanyl
and fentanyl derivatives, levomethadone, tramadol,
diclofenac, ibuprofen, naproxen, piroxicam, penicillamine
Antiallergics
pheniramine, dimethindene, terfenadine, astemizole,
loratidine, doxylamine, meclozine, bamipine, clemastine
Antibiotics/chemotherapeutics
of these: polypeptide antibiotics such as colistin,
polymyxin B, teicplanin, vancomycin; antimalarials such as
quinine, halofantrine, mefloquine, chloroquine,
virustatics such as ganciclovir, foscarnet, zidovudine,
aciclovir and others such as dapsone, fosfomycin,
fusafungin, trimethoprim
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Antiepileptics
phenytoin, mesuximide, ethosuximide, primidone,
phenobarbital, valproic acid, carbamazepine, clonazepam
Antimycotics
a) internal:
nystatin, natamycin, amphotericin B, flucytosine,
miconazole, fluconazole, itraconazole
b) external furthermore:
clotrimazole, econazole, tioconazole,
fenticonazole, bifonazole, oxiconazole,
ketoconazole, isoconazole, tolnaftate
Corticoids (internals)
aldosterone, fludrocortisone, betamethasone,
dexamethasone, triamcinolone, fluocortolone,
hydroxycortisone, prednisolone, prednylidene, cloprednol
methylprednisolone
Dermatics
a) Antibiotics:
tetracycline, erythromycin, neomycin, gentamicin,
clindamycin, framycetin, tyrothricin,
chlortetracycline, mipirocin, fusidic acid
b) Virustatics as above, furthermore:
podophyllotoxin, vidarabine, tromantadine
c) Corticoids as above, furthermore:
amcinonide, fluprednidene, alclomethasone,
clobetasol, diflorasone, halcinonide,
fluocinolone, clocortolone, flumethasone,
diflucortolone, fludroxycortide, halomethasone,
desoximethasone, fluocinonide, fluocortinbutyl,
fluprednidene, prednicarbate, desonide
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Diagnostics
a) radioactive isotopes such as Te99m, Inlll or I131,
covalently bonded to lipids or lipo:ids or other
molecules or in complexes
b) highly substituted iodine compounds such as e.g.
lipids
Haemostyptics/antihaemorrhagics
blood-clotting factors VIII, IX
Hypnotics, sedatives
cyclobarbital, pentobarbital, phenobarbital, methaqualone
(BTM), benzodiazepines (flurazepam, midazolam, nitrazepam,
lormetazepam, flunitrazepam, triazolam, brotizolam,
temazepam, loprazolam)
Hypophyseal, hypothalamic hormones, regulator peptides and
their inhibitors
corticotrophin, tetracosactide, chorionic gonadotropin,
urofollitropin, urogonadotropin, somatropin, metergoline,
bromocriptine, terlipressin, desmopressin, oxytocin,
argipressin, ornipressin, leuprorelin, triptorelin,
gonadorelin, buserelin, nafarelin, goselerin, somatostatin
Immunotherapeutics and cytokines
dimepranol-4-acetatamidobenzoate, thymopentin, a-
interferon, i3-interferon, y-interferon, filgrastim,
interleukins, azathioprine, cyclosporins
Local anaesthetics
internal:
butanilicaine, mepivacaine, bupivacaine, etidocaine,
lidocaine, articaine, prilocaine
external furthermore:
propipocaine, oxybuprocaine, tetracaine, benzocaine
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Antimigraines
proxibarbal, lisuride, methysergide, dihydroergotamine,
clonidine, ergotamine, pizotifen
Narcotics
methohexital, propofol, etomidate, ketamine, alfentanil,
thiopental, droperidol, fentanyl
Parathyroid hormones, calcium metabolism regulators
dihydrotachysterol, calcitonin, clodronic acid, etidronic
acid
Ophthalmics
atropine, cyclodrine, cyclopentolate, homatropine,
tropicamide, scopolamine, pholedrine, edoxudine,
idouridine, tromantadine, acyclovir, acetazolamide,
diclofenamide, metipranolol,
carteolol, timolol,
betaxolol, bupranolol, levobununol, carbachol,
pilocarpine, clonidine, neostigmine
Psychopharmaceuticals
benzodiazepines (lorazepam, diazepam), clomethiazol
Thyroid therapeutics
1-thyroxine, carbimazole, thiamazole, propylthiouracil
Sera, immunoglobulins, inocula
a) immunoglobulins generally and specifically, such as
hepatitis types, rubella, cytomegalovirus, rabies,
FSME, chickenpox, tetanus, rhesus factors
b) immunosera such as botulism antitoxin, diphtheria, gas
gangrene, snake venom, scorpion venom
c) inocula such as influenza, tuberculosis, cholera,
diphtheria, hepatitis types, FSME, rubella,
haemophilus influenzae, measles, neisseria, mumps,
poliomyelitis, tetanus, rabies, typhus
CA 02369594 2001-11-06
- 17 -
Sex hormones and their inhibitors
anabolics, androgens, antiandrogens, gestagens,
oestrogens, antioestrogens (tamoxifen etc.)
Cytostatics and metastasis inhibitors
a) alkylating agents such as nimustine, melphalan,
carmustine, lomustine, cyclophosphamide, ifosfamide,
trofosfamide, chlorambucil, busulphan, treosulphan,
prednimustine, thiotepa
b) antimetabolites such as cytarabine, fluorouracil,
methotrexate, mercaptopurine, thioguanine
c) alkaloids such as vinblastine, vincristine, vindesine
d) antibiotics such as aclarubicin, bleomycin,
dactinomycin, daunorubicin, doxorubicin, epirubicin,
idarubicin, mitomycin, plicamycin
e) complexes of B group elements (e.g. Ti, Zr, V, Nb, Ta,
Mo, W, Ru, Pt) such as carboplatin, cisplatin and
metallocene compounds such as titanocene dichloride
f) amsacrine, dacarbazine, estramustine, etoposide,
hydroxycarbamide, mitoxantrone, procarbazine,
temiposide
g) alkylamidophospholipids (described in J. M. Zeidler,
F. Emling, W. Zimmermann and H. J. Roth, Archiv der
Pharmazie [Pharmacy Archive], 324 (1991), 687)
CA 02369594 2001-11-06
- 18 -
h) ether lipids such as hexadecylphosphocholine,
ilmofosine and the like, described in R. Zeisig, D.
Arndt and H. Brachwitz, Pharmazie [Pharmacy] 45
(1990), 809-818.
i) taxans such as e.g. paclitaxel.
As mentioned above, the concentrated lipid particle
dispersions are especially suitable because of their low water
content for the production of various dosage forms such as
e.g. granules (e. g. for filling sachets), tablets, pellets,
capsules, dry products such as lyophilisates and spray-dried
products. The essential advantage is that only small amounts
of water need to be removed. This reduces the process time,
costs and above all, because of the shorter process time,
there is also less aggregation of particles.
Furthermore, because of the already sufficiently high
viscosity, the concentrated lipid particle dispersions may be
used directly as a topical medicinal form (e.g. gel) or after
the addition of viscosity-increasing substances or a liquid
oily phase.
The dispersions may, optionally after dilution with water, be
sprayed using commercially available devices (e. g. nasal
application) or atomised as an aerosol, e.g. using a Pariboy
(Example 9) or HaloLiteTM (Medic-Aid, England). A further
possible use is for the production of parenteral medicinal
forms, in particular if the volume to be applied is to be kept
minimal. Because of the high concentration of lipid particles,
small volumes can be implemented. The lipid particles can be
produced aseptically or subsequently sterilised using standard
methods.
Further active agents for incorporation into the lipid
particles according to the invention are any type of
odoriferous substances of natural, synthetic or semi-synthetic
CA 02369594 2001-11-06
- 19 -
origin. Examples which may be used include essential oils such
as citrus oil (Example 18), rose oil, lavender oil, bergamot
oil, balm oil, clove oil, cinnamon oil, orange oil, jasmine
oil, rosemary oil, aniseed oil, peppermint oil, sandalwood oil
or ylang-ylang oil, their isolated constituents such as e.g.
1,8-cineole, menthol, terpin hydrate, limonene, a-pinene,
eugenol and perfumes, in particular perfume oils. All perfumes
available on the market may be used, e.g. Allure (Example 19),
Coco, Egoiste, Chanel Nos 5, 19, 22 by Chanel, Miss Dior,
Dune, Diorissime or Fahrenheit by Dior, Roma, Laura, Venezia
by Laura Biagotti, Lair du temps by Nina Ricci, Chalimar by
Guerlain, Tresor by Lancome, Gio by Armani, Escape, Obsession,
CK One, CK be, Eternity by Calvin Klein, Berlin, Joop, Rococo,
All about Eve, what about Adam, Nightflight by Joop, KL,
Lagerfeld, Jako by Karl Lagerfeld, Extreme by Bulgari.
Besides odoriferous substances with a pleasant scent, it is
also possible to incorporate odoriferous substances with a
repulsive effect, e.g. repellents. Odoriferous substances with
a repulsive effect may be incorporated e.g. as warning
substances (protection against taking the product orally by
mistake) or as repellents, e.g. against insects. Examples of
natural repellents include citrus oils, eucalyptus oil and
camphor, and examples of synthetic repellents include N,N-
diethyltoluamide (DEFT), dibutyl phthalate, dimethyl
phthalate, 2-ethyl-1,3-hexanediol.
Further odoriferous substances include the so-called
attractants such as e.g. pheromones. Lipid particles with
attractants may e.g. be employed in cosmetics or in
insecticides. Examples of pheromones include androstenone and
androstenol; human pheromones are in particular used.
For insecticidal use or for killing small animals (e. g. fleas,
lice), the lipid particles may also contain poisons as an
active agent in addition to attractants. As an alternative,
attractant-containing lipid particles may be mixed with lipid
CA 02369594 2001-11-06
- 20 -
particles which contain poisons. Besides poisons which need to
be taken orally by the insect/small animal, contact poisons
may also be used. Because of their lipophilic nature, e.g. the
lipid particles adhere to the lipophilic chitin exoskeleton of
insects, and the contact poison can diffuse from the adhering
particles into the insect. Examples of poisons include
chlorinated hydrocarbons such as y-hexachlorocyclohexane,
pyrethrins, pyrethroids, alkyl phosphates such as paraoxon,
parathion, fenthion, dichlorvos and carbamates such as
butoxycarboxim, bendiocarb, methomyl, proxopur.
When oily odoriferous substances are incorporated, these oils
represent the liquid lipid component in the lipid particles,
that is to say the liquid odoriferous substance is mixed with
a lipid which is solid at room temperature, and in addition
one or more liquid lipids may also be added. Odoriferous
substances may also be dissolved in a liquid lipid and
subsequently blended with a solid lipid in order to produce a
particle. Dissolving in the molten solid lipid is also
possible as an alternative.
By incorporating the odoriferous substances into the lipid
particles, it is possible to control their release, and
prolonged release can in particular be achieved in a
controlled way. For instance, products based on emulsions
(oily odoriferous substances emulsified in water, odoriferous
substances dissolved in the oil phase of an O/W emulsion)
release the odoriferous substance relatively quickly. The
product loses its odoriferous effect. Incorporation into the
lipid particles reduces the discharge of odoriferous
substances and hence prolongs the product efficacy (Examples
18 and 19 ) .
Application examples for pleasant odoriferous substances
include cosmetic products (lotions, aftershaves etc.),
pharmaceutical products (increasing acceptance among patients)
CA 02369594 2001-11-06
- 21 -
and products for the hygiene and sanitary sectors (e. g.
scenting rooms for a prolonged period).
Further active agents for incorporation into the lipid
particles according to the invention include the various types
of markers (labels). Examples of such marking substances
include radioactive substances, for example iodated lipids
(iodated e.g. with iodine 131, iodine 123) and lipophilic
indium compounds (e. g. indium-111 oxine (8-hydroxyquinoline))
and technetium 99m, which are molecularly bound or complexed
or adsorbed. Such particles may be used for gamma
scintigraphy, e.g. after intravenous injection for
scintiography of the bone marrow and liver. Other markers
include coloured substances (dyes) or fluorescent substances
(fluorescent dyes).
An example of a coloured substance is Sudan red. Examples of
fluorescent substances include Nile red and fluorescein. In
general, lipid particles provided with markers may be used for
both in vitro diagnosis and in vivo diagnosis. Examples of in
vitro diagnosis include the characterisation of cell lines
e.g. determination of the phagocytotic activity after
differentiation of a cell line into a macrophage line. These
particles may also be used in diagnostic kits . Examples of in
vivo diagnosis include the marking of lymph nodes. For this
purpose, the particles are injected close to lymph nodes;
drainage into the lymph nodes and dyeing then take place. A
further example is the marking of body cavities and analysis
using fluorescence spectroscopy.
The lipid particles according to the invention may also be
used without the incorporation of active agents as diagnostics
in magnetic resonance (MR) tomography. Although the
introduction of magnetic resonance tomography has made it
possible to improve greatly diagnostic abdominal imaging,
reliably distinguishing the gastrointestinal tract from normal
or pathological surrounding tissue is even today often
CA 02369594 2001-11-06
- 22 -
difficult or impossible. MR images are in principle possible
without a contrast medium, but the signal intensities and
therefore the strength of the contrast are improved by T1 and
T2 contrast media, which influence the relaxation time. In
order make the tissue structures more easily distinguishable,
various substances have been proposed as contrast media. In
principle, they may in this regard to be divided into negative
contrast media (magnetites) and positive contrast media (e. g.
Magnevist). All substances tested to date can only satisfy the
requirement catalogue (low price, good acceptance and
toleration, lack of toxicity, no inducing of motion artefacts,
resistance to pH, homogeneous distribution throughout the
gastrointestinal tract, good contact with the intestinal wall,
contrast provision in all pulse sequences) to a limited
extent. Owing to their high fat content, SLNs are oral T1 MR
contrast media. The advantages are low price, good acceptance
(taste, tolerability), toleration, lack of toxicity
(physiological lipids), homogeneous distribution in the
gastrointestinal tract and good coverage of the intestinal
wall (particle size).
Of the SLN dispersions tested using a Bruker minispec pc120,
e.g. Witepsol H15 (C12-C18 hard fat) and Witepsol E85 (C12-C18
hard fat) are suitable as MR contrast media because of their
influence on the T1 relaxation times.
It is also possible to incorporate magnetites (Fe203, iron
oxides) into the lipid particles according to the invention as
markers. In particular, small iron oxide particles in the
range of approximately 1 to 3 nm are incorporated into the
lipid matrix. They can also be used as a contrast medium for
magnetic resonance tomography.
The above-described conversion of lipids of the lipid particle
matrix into the highly ordered stable f3 modification leads to
physical destabilisation, i.e. to particle aggregates (via
e.g. solid bridge formation). This is prevented in the
CA 02369594 2001-11-06
- 23 -
liquid/solid particles according to the invention in that a
part of the lipid is in a highly disordered state, i.e. liquid
state/melt (e. g. Miglyol, Example 12) or in a de facto liquid
state (a modification). The a modification has a low packing
density (K. Thoma, P. Serno, D. Precht,
Rontgendiffraktometrischer Nachweis der Polymorphie von
Hartfett [X-ray diffractometric investigation of the
polymorphism of hard fat], Pharm. Ind. 45, 420 - 425, 1983);
the fatty acid residues can oscillate relatively freely, so
that the state is similar to a melt (L. Hernqvist, Crystal
structures of fats and fatty acids, in: N. Garti, K. Sato,
Crystallisation and polymorphism of fats and fatty acids,
Marcel Dekker Inc., New York, Basle, 97-138, 1988).
The invention also uses the fact that, in fats of complex
composition (e.g. hard fat), a certain fraction is in the
liquid form even below the melting point (I. Hassan,
Phasenverhalten langkettiger Glyceride [Phase behaviour of
long-chain glycerides], Phd thesis, Christian Albrecht
University Kiel, 1988). The previous problem was, however,
that this liquid fraction promotes the conversion of the
metastable into the stable f3 modification (J. Schlichter-
Aronhime, N. Garti, Solidification and polymorphism in cacoa
butter and the blooming problems, in N. Garti, K. Sato,
Crystallisation and polymorphism of fats and fatty acids,
Marcel Dekker Inc., New York, Basle, 363-392, 1988; H.
Yoshino, M. Kobayashi, M. Samejima, Influence of fatty acid
composition on the properties and polymorphic transition of
fatty suppository bases, Chem. Pharm. Bull. 31, 237-246,
1983). In the present invention, it was surprisingly found
that
a) this transition does not occur with an appropriate
composition of the particle formulation (e.g. Example 13)
or
CA 02369594 2001-11-06
- 24 -
b) occurs faster (Examples 14-16) with a certain composition
of the particle formulation, which according to the
invention can be employed for the controlled release of
active agents.
The formation of the stable f3i/i3 modification leads to the
undesired effect that the active agents incorporated into the
particle matrix become displaced (so-called drug exclusion).
Active-agent crystals form in the lipid particle dispersions.
On transition from the disordered state (liquid or liquid-like
a modification) into the more stable f3i/i3 modification, the
number of liquid regions with dissolved drug is decreased,
together with the number of lattice defects (and therefore the
possibility of accommodating active-agent molecules in the
lipid matrix). Perfect crystals are formed and the active
agent becomes excluded. This is particularly pronounced in the
case of pure monoacid triglycerides, which form highly
crystalline solid lipid particles (Westesen, K., Bunjes, H.,
Koch, M. H. J., Physicochemical characterisation of lipid
nanoparticles and evaluation of their drug loading capacity
and sustained release potential, J. Control. Release 48, 223-
236, 1997).
The solid/liquid lipid particles according to the invention
remain even in highly concentrated dispersions as individual
particles; after production (e. g. Example 6) and even after
storage they have a liquid or a fraction (Example 13). The
liquid fraction can be deliberately increased by adding liquid
lipids (oils, e.g. triglycerides such as Miglyols) to solid
lipids. Small amounts of oil can be dissolved in the solid
lipid (i.e. distributed in molecularly dispersed form). When
the oil solubility in the solid lipid is exceeded, undissolved
oil molecules accumulate and compartments with liquid oil in
the nanometre range are formed (so-called nano-compartments).
Besides defects in the lipid lattice of a less perfect f3'
modification, active agent can here be incorporated in
dissolved form in the liquid nano-compartments. A carrier is
CA 02369594 2001-11-06
- 25 -
hence created, which consists of a solid lipid matrix with
incorporated nano-compartments of liquid lipid, the nano-
compartment carrier (NCC). Keeping as much lipid as possible
in disordered form in this nano-compartment carrier and
inhibiting the formation of 13i/i3 modification (i.e. avoiding
the formation of a solid lipid nanoparticle) promotes the
active-agent incorporation.
Through mixing liquid and solid lipids, the particles
according to the invention obtain a special internal structure
with increased disorder (liquid compartments, liquid
crystalline fractions, amorphous structures) and are no longer
completely crystalline.
The crystallinity of the particles is measured by comparing
their enthalpy of melting with the enthalpy of melting of the
bulk material of the solid lipid which is used, when it is in
its crystalline storage-stabilised modification, the f~ form (_
100s crystallinity). The enthalpy of melting of the particles
according to the invention is determined immediately after
production using differential scanning calorimetry (DSC) in
comparison with the bulk material. Calculating the enthalpy of
melting of the particles as a percentage of the enthalpy of
melting of the bulk material gives the crystallinity in per
cent, or the crystallinity index (e. g. 80% crystallinity
corresponds to 0.80 on the crystallinity index, See below).
Particles with a crystallinity index of 1.0 are completely
crystalline, particles with a crystallinity index of 0.50 or
higher are predominantly crystalline. Predominantly non-
crystalline particles have a crystallinity index of 0.50 or
less; in the case of almost completely x-ray amorphous lipid
particles, the crystallinity index tends to zero.
Predominantly crystalline particles and predominantly non-
crystalline particles are all partially crystalline, since at
least a part of the matrix is crystalline.
CA 02369594 2001-11-06
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It is possible to inhibit the formation of the stable f3i/i3
modification in that - as explained above - disordered lipid
(= without solid, highly ordered crystal structure) is present
in partially crystalline particles because of a liquid
fraction. Liquid lipids are mixed with solid lipids, in most
cases the liquid fraction being less than 50%. As an
alternative, the required lack of crystallinity may also be
created by deliberate production of amorphous particles.
Amorphous structures show no crystallinity. The particles are
formed when, as described above, a liquid lipid and a solid
lipid are mixed, the fraction of the liquid lipid for forming
these particles being generally at least 50%, possibly rising
to 99%. The oil is quasi-solidified while avoiding the
formation of an ordered crystalline structure. The particles
formed are therefore likewise partially crystalline
(predominantly non-crystalline), semi-solid to solid and x-ray
amorphous at a temperature of 21°C.
These particles are therefore unlike the lipid particles
described in the literature, which are produced
a) solely from solid lipids or
b) particles which are predominantly crystalline.
Eldem et al. (Eldem, T. et al., Optimization of spray dried
and congealed lipid micropellets and characterisation of their
surface morphology by scanning electron microscopy, Pharm.
Res. 8, 47 - 51, 1991) disclose microparticles consisting of
solid lipids, which are produced by spray-drying or spray-
congealing. The matrix material of these particles consists
exclusively of solid lipids. US-A-5 188 837 (bomb A.,
Liposphere for controlled delivery of substances, 1993)
describes lipid microspheres which consist of solid lipid
(e. g. a wax) and are covered with a phospholipid layer.
Tsutsumi et al. (J. Soc. Cosmet. Chem. 30, 345 - 356, 1979)
describe crystalline microparticles of hard paraffin which,
however, are physically unstable. Only as nanoparticles can
CA 02369594 2001-11-06
- 27 -
sufficient physical stability of these hard-paraffin particles
be obtained (de Vringer, T., Topical preparations containing a
suspension of solid lipid particles, European patent
application 0 506 197 A1, 1992). These and other nano- or
microparticles of lipids are always predominantly crystalline
(e.g. in the a or f3' crystal modification). Because of the
crystallinity of these particles, the take-up capacity for
active agents is usually limited (Westesen, K., et al.,
Physicochemical characterisation of lipid nanoparticles and
evaluation of their drug loading capacity and sustained
release potential, J. Control. Rel. 48, 223-236, 1997).
The mixing of liquid and solid lipids leads to disordered
structures with improved active-agent incorporation,
a) in the case of a liquid lipid fraction (oil) below 50%,
predominantly disordered liquid regions (nano-
compartments) being formed within a solid particle,
b) in the case of a liquid lipid fraction of 50% or more, the
disordered liquid lipid being solidified by the solid
lipid (solidified oil).
A characteristic of the invention is that disordered and
storage-stable structures are produced by adding liquid lipids
which lead to partially crystalline or predominantly non-
crystalline particles with semi-solid or solid aggregate
state.
Solidified oils are known from DE 197 07 309 Al (Clermont-
Gallerande, H., Feste kosmetische Zubereitung auf Basis
verfestigter Ole [Solid cosmetic preparation based on
solidified oils], 1998). However, these preparations are
water-free and do not constitute a dispersion. Instead, this
product is used in stick form.
A subsidiary object of the present invention was therefore to
provide carrier systems which consist of lipids with
CA 02369594 2001-11-06
- 28 -
physiological tolerability. These carrier systems are intended
to have a high loading capacity for active agents and are not
intended to change substantially in the course o:f storage.
It was therefore surprising, and not predictable by the person
skilled in the art, that the use of special suspensions, which
have liquid oils as substantial constituents, which are
amorphously solidified e.g. by waxes, according to Claim 1
could achieve this object.
Preferred refinements of this carrier system are in turn the
subject matter of the dependent claims.
The term suspension, or dispersion, is used here as a generic
term in its widest sense, and describes the distribution of a
discontinuous phase in a continuous phase. The discontinuous
phase may in this case be semi-solid, partially solid or
solid, and is partially crystalline or predominantly non-
crystalline. The continuous phase may be liquid, semi-solid or
solid, but not gaseous.
The oil phase of the carrier system contains at least two
components. The first essential constituent is a liquid oil.
The melting point of this oil is below 4°C. Preferred oils are
compounds of short-chain (fewer than 14 carbon atoms) fatty
alcohols. These include inter alia isopropyl myristate,
isopropyl palmitate, isopropyl stearate, octyldodecanol,
isopropyl alcohol C6_14 dicarboxylates, C14-20 branched-chain,
aliphatic fatty alcohols, C6_14 fatty acid triglycerides and
diglycerides, C12-16 octanoates, tridecyl salicylates and oils
of the Crodamol~ group.
The second essential constituent of the oil phase is a
lipophilic solidifying substance which is solid at 37°C. This
is selected, in particular, from the group consisting of
lipids having a melting point above 40°C and optionally
lipophilic gelling agents (e. g. hydrophobic polymers).
CA 02369594 2001-11-06
- 29 -
Suitable substances include esters of long-chain fatty
alcohols with long-chain fatty acids, waxes, certain
glycerides and long-chain fatty alcohols, in each case having
a melting point above 40°C. In particular, this substance is
selected from the group consisting of carnauba wax,
hydroxyoctacosanyl hydroxystearate, Chinese wax, cetyl
palmitate, beeswax and similar waxes. Further examples of
these solidifying substances include Cao-ao di- and
triglycerides, including those which contain unsaturated fatty
acids, CZQ_40 fatty alcohols, Cao-4o fatty amines and their
compounds, sterols.
The liquid oil and the structuring agent are preferably mixed
in a proportion of from 99 + 1 to 50 + 50, in particular in a
proportion of from 95 + 5 to 80 + 20. The mixture of polar oil
and structuring agent is, after heating the components
together to 90°C and subsequently cooling to ambient
temperature while stirring, semi-solid or solid at 21°C. The
mixture is predominantly an amorphous, non-crystalline solid
or semi-solid substance. The term solid is here defined as
follows, after Bauer et al. (Bauer et al., Pharmazeutische
Technologie, 4th edition, Georg Thieme Verlag Stuttgart, New
York, 1993, page 43):
"Solids are shape-stable bodies which are elastic in response
to moderate mechanical forces". Semi-solid substances "are
distinguished in that they have only limited shape stability"
(Bauer et al., Pharmazeutische Technologie, 4th edition, Georg
Thieme Verlag Stuttgart, New York, 1993, page 253). The
amorphous state is demonstrated by the fact that the mixture
has no x-ray reflections, or only very weak or :broad ones, in
comparison with the crystalline reference substance cetyl
palmitate. The absence of crystalline fractions can inter alia
be made visible by using a microscope with polarised light. In
this case, crystalline regions are in general illuminated
whereas amorphous or liquid regions remain dark. The mixture
should therefore preferably show no luminous regions through
CA 02369594 2001-11-06
- 30 -
the microscope under polarised light. The crystallinity in the
mixture can be measured using dynamic differential scanning
calorimetry (DSC) . The crystallinity index (CI) can be defined
as the ratio between the crystallinity of the raw material and
the crystallinity of the mixture of the two components. The
crystallinity is in this case determined by the height of the
melting peak (e. g. in mW) per gram of the crystalline lipid.
The height of the melting peak of the raw material of the
solidifying agent is denoted "raw", and the height of the
melting peak in the mixture is denoted "mix"
mix
CI = _____________
raw
The crystallinity index is advantageously below 0.5.
The oil phase may contain mixtures of the said components and,
besides the said two essential components, further lipophilic
substances so that the resulting mixture, after heating the
components together to 90°C and subsequently Gaoling them to
room temperature while stirring, is solid or semi-solid and
remains predominantly amorphous. Examples of further
components include lipophilic drugs and cosmetic ingredients,
plant and natural oils and fats, lipophilic antioxidants,
sunscreens, essential oils, perfumes, plant extracts etc.
A third essential constituent of the carrier system according
to the invention is water or a liquid which is miscible with
water. In a preferred embodiment of the present invention, the
water phase contains a gel-forming, structuring additive,
which renders the water phase semi-solid and has a yield point
of 5 Pa or above at 21°C (measured e.g. using a rheometer).
Suitable structuring additives include hydrophilic polymers,
certain inorganic gelling agents and amphiphilic substances.
Examples of polymers include alginates, cellulose derivatives,
xanthan gum, starch and starch derivatives. Examples of
inorganic gelling agents include Aerosil~ types and
CA 02369594 2001-11-06
- 31 -
bentonites. Examples of amphiphilic substances having a
viscosity-increasing effect include glycerol monostearate and
poloxamer 127. Preferred structuring agents are
polyelectrolytic polymers such as e.g. polyacrylic acids,
carboxymethylcellulose or carrageenan.
The water phase may contain further additives such as e.g.
hydrophobic or amphiphilic drugs or cosmetic ingredients,
water-soluble antioxidants, preservatives, humectants or plant
extracts.
The suspension furthermore contains, as a matter of necessity,
substances which increase the physical stability of the
suspension. These may be the gel-forming polymers already
mentioned above or amphiphilic substances (emulsifying
agents). Suitable emulsifying agents include myristyl alcohol,
cetyl alcohol, stearyl alcohol, polysorbates, sorbates, block
polymers (e. g. poloxamers), glycerol fatty monoacid esters
(e. g. glycerol monostearate), esters of polycarboxylic acids
and fatty alcohols, or mono- and diglycerides of fatty acids
esterified with lactic acid, citric acid or tartaric acid
(e.g. glycerol stearate citrate). The use of a combination of
at least two emulsifying agents is advantageous. In this case,
one emulsifying agent should be charged (positively,
negatively or ampholytically). Examples of this include
glycerol stearate citrate and quaternary ammonium compounds
(cetylpyridinium chloride).
The oil phase, water phase and the suspension stabilisers are
mixed in order to obtain intimate distribution of the oil
phase in the continuous water phase. The size of the oil
droplets is typically between 1 ~.m and 100 ~,m. The continuous
water phase of the suspension may be characterised e.g. by a
fast dissolving capacity for hydrophilic dyes or by
miscibility with water. The water phase fraction
advantageously.constitutes 40 - 95% of the total suspension.
CA 02369594 2001-11-06
- 32 -
The lipid particles having a large or predominantly liquid
fraction in the lipid mixture (in general > 500) will be
explained in more detail with reference to Examples 21 to 26.
The active agent can be released as desired by the transition
(crystallisation), induced in a controlled way, into the
stable f3 modifications of lipids (Examples 14-16). Stimuli for
initiating this transition include adding electrolytes,
increasing the temperature or removal ~f water from the NCC
dispersion.
An example of water removal is the drying of particle
dispersions after topical application to the skin. In the case
of sufficiently sensitive systems, the modification transition
and the active-agent release may actually be induced by the
electrolytes present on the skin. This is of particular
interest for active agents such as cyclosporin (Example 6)
which, after topical application, do not penetrate
suf f iciently into the skin to be able to treat a . g . psoriasis
successfully. In contrast to other particulate carriers, in
which the release is based on pure diffusion, with NCCs the
active agent is released actively from the carrier. The
driving force is the induced formation of perfectly
crystalline particles, in which there is no longer any space
for the active-agent molecules. The drug (e. g. cyclosporin)
becomes expelled into the outer phase (e. g. water of the NCC-
containing lotion or cream), in which it has low solubility.
As a result, the water phase becomes supersaturated with drug
and the pressure for the drug's diffusion into the skin is
consequently increased (= increase in the thermodynamic
activity of the active agent) (Fig. 13). NCCs are therefore
suitable, in particular, for active agents with
bioavailability problems, e.g. cyclosporins (e. g. cyclosporin
A) and structurally related molecules. Mixtures of solid
lipids (e. g. Imwitor and Compritol) and liquid lipids (oils
(e. g. castor oil, olive oil, maize oil, softigen, isopropyl
CA 02369594 2001-11-06
- 33 -
myristate, octyldodecanol and Miglyols)) have proved to be
especially suitable for cyclosporins.
The particles according to the invention may be produced at a
high solids concentration as a dispersion. This avoids the
above-described disadvantages with the processing of previous
low-concentration lipid particle dispersions into other
medicinal forms such as e.g. topical dosage forms and
cosmetics (creams), oral dosage forms (such as e.g. tablets,
pellets and capsules) and in the case of parenterals. Lipid
particle dispersions not only can be incorporated into
tablets, film tablets and coated tablets, but may also be
coated onto them. For this purpose, the tablets or coated
tablets are sprayed with the particle dispersion (e.g. in a
ball coater (Glatt), Wurster apparatus, fluid-bed drier,
Accela Coat) or the lipid particle dispersion is added in a
tablet-coating pan. Non-loaded lipid particles may be used to
produce a protective film (e. g. against oxygen and humidity),
a film for altering the active-agent release or for polishing
coated tablets and film tablets. Particles loaded with active
agent may provide controlled release of a separate medicament
dose, e.g. an initial dose.
Coated tablets and film tablets have hitherto been polished by
adding wax balls (e. g. carnauba wax) or by spraying on waxes
in organic solvents. The use of lipid particle dispersions
(micro- or nanometre particle size) leads to finer
distribution of the lipid on the coated-tablet surface in
comparison with wax balls (diameter e.g. 1 cm) and avoids
organic solvents. Low-concentration lipid particle dispersions
cannot be used for this purpose since, because of the high
water content, e.g. the coated-tablet surface may partially be
dissolved. The particle dispersions according to the invention
are, by contrast, distinguished by their relatively low
proportion of water.
CA 02369594 2001-11-06
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When producing lipid particles in non-aqueous, preferably oily
media and liquid polyethylene glycols (e.g. PEG 400 and PEG
600), soft or hard gelatine capsules may be filled directly
with the dispersions. when producing in a PEG which is solid
at room temperature (e. g. PEG 6000), the solidified product
(dispersion of lipid particles in solid PEG) may be ground,
and hard gelatine capsules may be filled with it in powder
form.
Examples
Example 1: Production of a 40% lipid particle d i s p a r s i o n
(solids content 45%):
The composition of the lipid particle dispersion was 40% cetyl
palmitate, 5% saccharose ester S-1670 (Mitsubishi-Kagaku Foods
Corporation, Tokyo, Japan) and water to 100%. The lipid was
heated to 90°C and mixed using a rotor-stator stirrer (Ultra-
Turrax, Janke & Kunkel, Germany) at 8000 revolutions per
minute for two minutes with the hot aqueous solution of the
surfactant. The raw emulsion obtained was then :homogenised in
a Micron LAB 40 at 500 bar and in 3 cycles at 80°C. The
product was white and of creamy consistency. After cooling and
crystallisation of the lipid nanoparticles, the particle size
in the product was measured. The diameter was 246 nm and the
polydispersity index was 0.179 (measurement method: photon
correlation spectroscopy (PCS), device: Zetasizer 4, Malvern
Instruments, UK).
Example 2: Production of a 50% lipid particle dispersion
(solids content 55%):
The formulation of Example 1 was used, the lipid fraction
having been increased from 40% to 50%. Production and
homogenisation took place as in Example 1. The product
CA 02369594 2001-11-06
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obtained was diluted in order to determine the particle size;
the PCS diameter was 325 nm and the polydispersity index was
0.190.
Example 3: Production of a 40% lipid particle dispersion
(solids content 45%) using a rotor-stator stirrer:
Composition of the lipid particle dispersion: 40% fat, 5%
saccharose ester S-1670 (Mitsubishi-Kagaku Foods Corporation,
Tokyo, Japan) and water to 100%. 24 g of an aqueous surfactant
solution was heated to 80°C, and 4 g of molten lipid were
added and dispersed for 2 minutes using an Ultra-Turrax (Janke
& Kunkel, Germany) at 8000 revolutions per minute. A further 4
g of molten lipid were then added, the dispersion conditions
being as before. Successive addition of, in each case, 4 g of
molten lipid continued until the total lipid content was 40%.
After cooling and crystallisation of the lipid particles, a
particle size measurement was carried out in water. The
diameter 50% was 12.25 um (measurement method: laser
diffractometry, device: Mastersizer E, Malvern. Instruments,
UK). A volume distribution curve was measured.
Example 4: Production of a 70% lipid particle dispersion
(solids content 75%):
The formulation of Example 3 was employed with 5% saccharose
ester, but the lipid content was increased from 40% to 70%.
Production took place as in Example 3, 4 g of lipid being
added successively in each case until the maximum lipid
concentration was 70%. After cooling, a diameter 50% of 20.68
~m was measured (laser diffractometry as Example 3).
Example 5: Storage stability of the highly concentrated lipid
particle dispersions:
The dispersion of Example 1 was stored at room temperature for
14 days. Determining the particle size using PCS gave a
CA 02369594 2001-11-06
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diameter of 243 nm and a polydispersity index of 0.203. There
was no significant particle size increase, and the dispersion
is physically stable in the highly concentrated form.
Example 6: Production of a drug-containing 50% lipid particle
dispersion (solids content 55%):
The composition of the lipid particle dispersion was 48%
Imwitor 900, 2% cyclosporin A, 5% Tween 80 and water to 100%.
The lipid and medicament were heated to 90°C and mixed using a
rotor-stator stirrer (Ultra-Turrax, Janke & Kunkel, Germany)
at 8000 revolutions per minute for 2 minutes with the hot
aqueous solution of the surfactant. The raw emulsion obtained
was then homogenised in a Micron LAB 40 at 500 bar and in 3
cycles at 80°C.
Example 7:
The cyclosporin-loaded lipid particle dispersion was examined
with respect to crystalline status using differential scanning
calorimetry (DSC). The measurements show that the lipid
particles are predominantly in a modification (onset
temperature 51.5°C, peak maximum 58.7°C), whereas the pure
lipid has predominantly Q modification (onset temperature
54.2°C, peak maximum 61.9°C) (Fig. 5).
Example 8: Production of a 80% lipid particle dispersion
(solids content 85%)
The formulation of Example 1 was used, the lipid fraction
being increased from 40% to 80%. A 50% lipid particle
dispersion was first produced in a similar way to Example 1.
10% of lipid was in each case added successively in sub-steps
to the product obtained while stirring by means of a rotor-
stator stirrer at 8000 revolutions per minute until an 80%
lipid particle dispersion was obtained. A diameter 99% of
CA 02369594 2001-11-06
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77.66 ~Cm was measured after cooling (laser diffractometry as
Example 3).
Example 9: Atomisation of a l00 lipid particle dispersion by
means of a Pariboy (Paul Ritzau Pari-Werk GmbH,
Starnberg, Germany):
The composition of the lipid particle dispersion was loo cetyl
palmiate, 1.2o Tego Care 450 and water to 100°x. Production and
homogenisation took place as in Example 1. The product
obtained was atomised by means of a Pariboy and the resulting
aerosol was collected in a beaker. The diameter 50% was 0.28
~,m before and 0.30 ~,m after atomisation (laser diffractometry
as Example 3).
Example 10: Production of liquid/solid particles using
Imwitor:
The composition was loo Imwitor, 5% Miglyol 812, 0.5% retinol,
2.5a Miranol (sodium cocoamphoacetate) and 82'a water. The
lipids Imwitor and Miglyol were mixed in the molten state at
90°C and then particles were produced as in Example 1. The PCS
diameter was 188 nm and the polydispersity index was 0.266.
The wide-angle x-ray diffractogram (Fig. 5, left) confirms the
predominant presence of the fat in the liquid state (a
modification) .
Example 11: Production of liquid/solid particles using
Compritol:
Production took place as in Example 10, the lipid Imwitor
having been replaced by Compritol. The Miranol concentration
was here 1.50. The PCS diameter was 225 nm and the
polydispersity index was 0.205.
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Example 12: Production of liquid/solid particles with
different proportions of liquid lipid:
Compritol particles were produced as described in Example 11.
The lipid fraction was constant at 15% (solid lipid Compritol
+ oil Miglyol) in the aqueous dispersion, the proportion of
oil to solid lipid having been changed. Particles were
produced with 8.3%, 16.7%, 28% and 38% oil fraction in the
lipid (i.e. 91.7%, 83.3%, 72% and 62% Compritol). At a low oil
fraction (8.3%) in the mixture, the oil dissolves
predominantly in the solid lipid (molecularly disperse
distribution) and only a few nano-compartments of liquid oil
result. Oil distributed in a molecularly disperse form cannot
crystallise; crystallisation and release of crystal lattice
energy occur only when there is a sufficiently great
accumulation of molecules (e.g. nano-compartment), so the
measured enthalpy of melting, calculated in terms of the total
amount of oil incorporated, is far below the theoretical value
of 12 J/g and close to zero (Fig. 6, left). when the oil
fraction is increased, the take-up capacity threshold of the
solid lipid matrix for oil molecules is reached, and
predominantly small regions with liquid oil are formed. These
nano-compartments can crystallise and the enthalpy increases
linearly from a 16.7% to 38% oil fraction (Fig. 6).
The x-ray diffractograms of the particles confirm that,
besides the liquid lipid in a modification detected by DSC,
there is also solid lipid in the unstable i3' modi-fication
(peaks at 0.38 nm and 0.42 nm spacing, Fig. 7).
Example 13: Conservation of the lipid fraction in lipid
particles by inhibiting the transformation of
the lipid into the stable f3 modification:
20 parts of aqueous SLN dispersion from Example 10 were
incorporated by stirring, into 80 parts of a cosmetic O/W
cream (Nivea Visage, Beiersdorf, Hamburg, Germany). After 168
CA 02369594 2001-11-06
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days of storage at room temperature, the x-ray diffractogram
showed no change in comparison with the day after production
(Fig. 5) .
Example 14: Controlled crystallisation of the lipid
fraction and transformation of cx/f3' into the
stable f3i/i3 modification by electrolytes:
parts of glycerol and 70 parts of water were added to 20
parts of the Imwitor particles from Example 10. 0.4% of
Carbopol 940 (polyacrylic acid) are added to this mixture as a
gelling agent and 0.1% of sodium hydroxide was thin added as
an electrolyte. Immediately after production, the liquid/solid
lipid particles, still unchanged, show a pronounced liquid
fraction of a modification (Fig. 8, left) which becomes a
solid lipid particle of the stable f~i/f3 modification under the
influence of the electrolyte (Fig. 8, right).
Example 15: Controlled transformation of a/f3' into the
stable i3i/f3 modification by water removal:
A Compritol particle dispersion was produced as in Example 11,
the Miglyol containing 10% retinol. In order to investigate
the release, 200 ~cl of aqueous SLN dispersion were introduced
into a continuous flow Franz cell (Crown Scientific, US-
Sommerville) (acceptor medium: isotonic phosphate buffer pH
7.4, flow rate medium: 1.0 ml/h, temperature: 37°C, membrane:
cellulose nitrate filter impregnated with isopropyl
myristate). The x-ray diffractograms show that the dilution by
water leads to formation of a solid lipid particle with stable
iii modification (Fig. 9, peak at 0.46 nm spacing). As the
transition into a solid particle with fewer crystal defects
progresses, increasingly more drug is expelled from the
particle, that is to say the release (drug flux) increases
with time (= increasing degree of crystallisation) (Fig. 10).
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For comparison, a nanoemulsion with a comparable drop size was
produced by replacing Compritol with Miglyol in the production
process (PCS diameter: 186 nm, PI 0.113).
Example 16:
Retinol-loaded particles were produced as in Example 15. 10
parts of glycerol and 70 parts of water were added to 20 parts
of the particle dispersion. 0.5% of xanthan gum was added to
this mixture. The hydrogel formed was investigated in the
Franz cell as in Example 15. As a result of the water
dilution, the more stable f3i modification also formed in the
hydrogel (Fig. 11), the drug was expelled from the lipid
matrix to an increasing extent and the flux (drug release)
increased with time (Fig. 12).
Example 17: Production of a dispersion for polishing
coated pills:
Lipid particles based on carnauba wax were produced by high
pressure homogenisation (31% carnauba wax, 3% surfactant,
water). Production was carried out using a Micron LAB 40 at
95°C, 500 bar and 3 cycles. The PCS diameter was 420 nm and
the polydispersity index was 0.185.
Example 18: Prolonged active-agent release of citrus oil
from stearic acid particles in comparison with
Miglyol emulsions:
A lipid particle dispersion consisting of 10°s (m/m) stearic
acid, 1% (m/m) citrus oil, 1.2% (m/m) Tween~ 80 and water was
produced by high-pressure homogenisation. The mixture of lipid
and emulsifying agent was melted at 75°C and dispersed in the
aqueous solution using an Ultra-Turrax T25 with dispersing
tool S25, Janke & Kunkel (8000 rpm, for 1 minute). The raw
emulsion obtained was then homogenised using an APV Gaulin LAB
40 homogenises at 500 bar in 3 cycles at 75°C. Lipid particles
CA 02369594 2001-11-06
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having a mediam LD diameter (LD d50%) of 215 nm resulted. As a
comparison, an emulsion system was similarly produced, the 10%
stearic acid having been replaced by loo Miglyol 812. The LD
d50a was here 195 nm. In vitro release experiments at 32°C,
which were evaluated using W spectrophotometry, confirmed
prolonged release from the SLN dispersion (no burst release as
in the case of the emulsion). After 6 hours, the cumulative
release from the SLN dispersion was reduced by 50o in
comparison with the emulsion. (Fig. 14).
Example 19: Prolonged active-agent release of the perfume
oil Allure (Chanel) from stearic acid
particles in comparison with Miglyol
emulsions:
A lipid particle dispersion consisting of l00 (m/m) stearic
acid, to (m/m) Allure, 1.2% (m/m) Tween~ 80, and water was
produced by high-pressure homogenisation in a similar way to
Example 18. Lipid particles having an average PCS diameter of
336 nm and a polydispersity index 0.137 resulted. As a
comparison, an emulsion system was similarly produced, the 10%
stearic acid having been replaced by loo Miglyol 812. In vitro
release experiments at 32°C, which were evaluated using W
spectrophotometry, confirmed prolonged release from the SLN
dispersion. After 6 hours, 1000 of the perfume oil had already
been released from the emulsion system; the release from the
SLN dispersion was, however, only 75o at this time.
Example 20:
Lipid particle dispersions were produced with witepsol H15
(Clz-Cle hard fat) and Witepsol E85 (Clz-C18 hard fat) by high-
pressure homogenisation (three cycles, 500 bar, production
temperature 85°C, device LAB 40) . The particle sizes were 119
nm and 133 nm (PCS diameter). The lipid particles were
examined with respect to the change in the relaxation times T1
and T2 using a Bruker mini-spec pc 120. The relaxation times
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were T1 - 0.1498 s and T2 - 0.0707 s (Witepsol E85) and T1 -
0.1577 s and T2 - 0.1191 s (Witepsol H15).
Example 21:
This example shows in 1 the composition of a typical
suspension, which complies with the claims of this invention.
As a comparative example, the formulation Vl is indicated
which does not comply with the claims of this invention.
1 V1
Vaseline - 5.0%
Paraffin oil - 10.0%
Dimeticon 100 - 5.0%
Jojoba oil - 4.0%
Isopropyl myristate 10.0% -
Medium chain triglycerides 10.0% -
Hydroxyoctacosanyl hydroxystearate 4.0% -
Retinaldehyde 0.2% 0.2%
Glycerol monostearate 0.3% 0.3%
Cetyl alcohol 0.5% 0.5%
Polysorbate 80 0.5% 0.5%
Glycerol stearate citrate 2.0% 2.0%
Sorbitol 5.0% 5.0%
Polyacrylic acid 0.5% 0.5%
Sodium hydroxide to adjust to adjust
the pH the pH
(pH 6 - 7) (pH 6 -
7)
Sodium chloride 0.5% 0.5%
water to 100% to 100%
The lipophilic components, including the active agent, and the
hydrophilic components, including the emulsifying agent but
without the polyacrylic acid, are heated separ<~tely to 90°C
and mixed at 90°C. The mixture is dispersed at this
temperature for five minutes using an Ultra-Turrax at 10,000
revolutions per minute. After cooling to 40° while stirring,
the polyacrylic acid was added, dispersed for a further 1
minute using the Ultra-Turrax and the suspension is
subsequently cooled to ambient temperature while stirring.
CA 02369594 2001-11-06
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Example 22:
This example demonstrates the possibility of stabilising
unstable active agents by means of the invention. The
comparative formulation V1 shows no amorphously solidified oil
phase and and does not therefore have a composition according
to the invention. The stabilities of the two :retinaldehyde-
containing preparations from Example 21 are listed in Table 1.
Storage takes place at room temperature (RT) or 40°C in closed
glass vessels which contain 1/3 the preparation and 2/3 air.
The values are expressed in per cent of the starting
concentration. The contents were determined using W
spectroscopy at a detection wavelength of 325 nm.
Table 1
Time (d) 14 days 28 days 84 days
RT 40°C RT 40°C RT 40°C
1 92.6 75.1 89.2 64.2 82.8 35.7
V1 85.9 62.8 76.7 35.2 60.1 9.0
Table 1 clearly shows that, after 12 weeks of storage at 40°C
for the carrier system according to the invention, a many
times higher amount of the active agent was fo~.znd that in a
comparison emulsion.
Example 23:
This example demonstrates the possibility of reducing the
irritant effect of incorporated active agents. The active
agent used, benzyl nicotinate, causes hyperaemia of the skin,
which can be identified by reddening of the relevant skin
areas. 8 mg of the preparations 2 and V2 were respectively
distributed uniformly without pressure on two skin areas of
size 2 cm x 2 cm. The reddening of the two areas was compared
at specific time intervals and assessed on a scale of from 0
CA 02369594 2001-11-06
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(no skin reddening) to 4 (very strong skin reddening). The
preparations 2 and V2 had the following compositions:
2 V2
Isopropyl myristate 10.0% 10.0%
Medium chain triglycerides 10.0% 10.0%
Hydroxyoctacosanyl hydroxystearate 5.0% -
,Toj oba oil - 5 . 0 %
Benzyl nicotinate 2.5% 2.5%
Glycerol monostearate 0.3% 0.3%
Cetyl alcohol 0.5% 0.5%
Polysorbate 80 0.5% 0.5%
Glycerol stearate citrate 2.0% 2.0%
Sorbitol 5.0% 5.0%
Polyacrylic acid 0.8% 0.8%
Sodium hydroxide to adjust to adjust
the pH the pH
(pH 7 - 8) (pH 7 - 8)
Sodium chloride 0.5% 0.5%
Water to 100% to 100%
Preparation 2 has a composition according to the invention,
and possesses a solidified oil phase, so that the active agent
is immobilised better. Preparation V2 does not have a
composition according to the invention. The solid wax
hydroxyoctacosanyl hydroxystearate of preparation 2 was
replaced in v2 by the liquid wax j of oba oil, so that the oil
phase remains completely liquid and the active agent cannot
consequently be immobilised.
The profile of the skin reddening as a function of time is
represented in Fig. 15. The arithmetic means of 4 people (2
male, 2 female, in each case left forearm, no skin diseases)
are plotted. Fig. 15 shows that in the case of the emulsion 2
according to the invention (solid line) the reddening sets in
CA 02369594 2001-11-06
45 -
slower and the peak of the profile is smoothed in comparison
with V2 (broken line). This implies a reduction in the
irritant effect of the active agent by its incorporation into
the carrier system.
Example 24:
This example demonstrates a possible method of detecting the
solid nature of the oil droplets in the suspension. The
mixture of solidifying wax and liquid oil must, as described
above, be an amorphous solid or semi-solid substance. The
shape stability, as defined above, can be demonstrated
macroscopically in the coarse mixture. A possible method which
can detect the solid nature of the oil droplets, some of which
are only a few micrometres in size, in the suspension will be
described below. It involves proton resonance spectroscopy (1H-
NMR). This can measure the mobility of the fat molecules. Very
mobile molecules lead to very intense and sharp resonance
signals. Very immobile molecules, on the other hand, produce
resonance signals only of weak intensity and large signal
width (Riicker et al., Instrumentelle pharmazeutische Analytik
[Instrumentational pharmaceutical analysis], 2nd edition,
Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, page 172,
1992). In this method, the carrier system according to the
invention is compared with an emulsion not according to the
invention (reference emulsion), in which the solidifying
substance is replaced by a corresponding amount of the liquid
wax jojoba oil. The signals used for evaluation are those
between 0.8 and 2.6 ppm, which correspond to the signals of
the protons of the fatty acid chains, in particular the
strongest signal at approximately 1.25 ppm. The intensity is
the height of these signals and the linewidth is the width
measured at half the height of the signal. The suspension
according to the invention shows the less intense and broader
signals compared with the reference formulation. The
solidification of the oil droplets is shown in pa=titular by:
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- the linewidth of a proton signal of the carrier system is
at least twice as wide as the linewidth of the
corresponding signal of the reference emulsion and/or
- the intensity of a signal of the carrier system is at most
half the intensity of the corresponding signal of the
reference emulsion.
Figure 16 represents the 1H-NMR spectra of suspension 2 (upper
spectrum) and of the comparison formulation V2 (lower
spectrum) from Example 23. For suspension 2, the intensity of
the signal at 1.22 ppm is 2.48 units and the linewidth is
0.058 ppm. The reference formulation V2 has an intensity of
5.82 units and a linewidth of 0.037 ppm for the signal at 1.22
ppm.
The solidifying substance can build a network in the oil
droplets and hence create the shape stability. The solidifying
substance can also be distributed diffusely in the matrix of
the liquid oil and hence create the shape stability.
Example 25:
This example illustrates the above-defined crystallinity index
(CI). The raw material is measured first. The height of the
melting peak of e.g. hydroxyoctacosanyl hydroxystearate at
76.5°C is 1245.9 mW per gram of hydroxyoctacosanyl
hydroxystearate (measured using a differential heat flux
calorimeter). Secondly, 70 parts of the oil consisting of
medium chain triglycerides (Miglyol 812) is mixed with 30
parts of hydroxyoctacosanyl hydroxystearate, this mixture is
heated to 90°C and allowed to cool while stirring. Measurement
using a differential heat flux calorimeter now gives a height
of the melting peak at 68.9°C of 310.6 mW per gram of
hydroxyoctacosanyl hydroxystearate. The CI is therefore
calculated as:
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310.6 mW
CI -__ _____________ _ 0.25
1245.9 mW
The crystallinity of the raw substance is therefore
drastically reduced in the mixture. The oil phase is
predominantly non-crystalline.
Example 26:
X-ray diffractometry can be employed to demonstrate the
amorphous nature of the solidified oil droplets. Fig. 17 shows
x-ray diffractograms for a 2 theta angle range - 18 - 26°.
Fig. 17 shows at the top (1) the diffractogram of the
formulation V2 from Example 23, in the middle (2) the
formulation 2 from Example 23 and at the bottom a
corresponding amount of crystalline cetyl palmitate. The
formulation V2 is, as expected, predominantly x-ray amorphous
(liquid oil droplets) (1). The formulation 2 is likewise x-ray
amorphous, in spite of the hydroxyoctacosanyl hydroxystearate
present in the solid form, and therefore meets the
requirements of this invention (2). Crystalline cetyl
palmitate, on the other hand, shows two intense reflections
and is therefore not amorphous (3). A definition of
predominantly amorphous which may in particular be used in the
sense of this invention is that the intensity (height) of a
reflection of the suspension amounts to at most 50% of the
intensity of the reflection of the corresponding solid raw
material, in each case expressed in terms of the same amount
by weight of the raw material.
Brief Description of the Figures:
Fig. 1: structure of a gel framework of spherical Aerosil
(silicon dioxide) particles.
Fig. 2: structure of a polydisperse gel framework of
magnesium-aluminium silicate (bentonite).
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Fig. 3: formation of solid bridges upon contact of lipid
particles by solidification of the outer shell.
Fig. 4: structure of a biamphiphilic cream.
Fig. 5: x-ray diffractograms of the Imwi.tor particle
dispersion in creams (Examples 10 and 13) on the
day after production (left) and after 168 days of
storage (right).
Fig. 6: heat of crystallisation (J/g) of the liquid lipid
in the particles from Example 12 as a function of
the oil content in the lipid mixture consisting of
liquid Miglyol and solid Compritol. Comparison:
emulsion produced by using Miglyol, i.e. lipid
consists of 100% oil. (Analysis using DSC
(differential scanning calorimetry), temperature
range: -20 to -60°C, cooling rate: 5 K/min,
Mettler Toledo DSC 821e, Mettler, Giel3en).
Fig. 7: x-ray diffractogram of the particles with
increasing oil fraction from Example 12. From top
to bottom: oil fraction in the lipid: 38%, 28%,
16.7% and 8.3%.
Fig. 8: x-ray diffractograms of the Imwitor particle
dispersion immediately after incorporation into a
Carbopol gel and after transformation. into a solid
particle by electrolyte addition (Example 13).
Fig. 9: x-ray diffractogram of the particle dispersion
from Example 14 before introduction into the Franz
cell (curve at the bottom) and after water
evaporation over the measurement period of 24
hours (top).
CA 02369594 2001-11-06
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Fig. 10: increasing retinol flux from the dispersion with
liquid/solid particles from Example 14 in the
course of the transformation to the solid particle
in J3i modification. For comparison: constant
release of retinol from liquid particles (oil
droplets of an emulsion).
Fig. 11: x-ray diffractogram of the hydrogel of Example 15
containing liquid/solid lipid particles before
introduction into the Franz cell (curve at the
bottom) and after water evaporation over the
measurement period of 24 hours (top, arrow: peak
for iii modification) .
Fig. 12: increasing retinol flux from the hydrogel of
Example 15 containing liquid/solid lipid particles
in the course of the transformation to the solid
particle in f3i modification. For comparison:
constant release of retinol from liquid particles
(oil droplets of an emulsion) in an identical
hydrogel base.
Fig. 13: model for the active-agent release from
cyclosporin/lipid particles (Example 6).
Fig. 14: release of citrus oil at 32°C from the SLN
dispersion and the emulsion.
Fig. 15: reduction in the irritant effect of the active
agent by its incorporation into the carrier
system.
Fig. 16: 1H-NMR spectra of suspension 2 (upper spectrum) and
of the reference formulation V2 (lower spectrum)
from Example 23.
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Fig. 17: x-ray diffractograms for a 2 theta angle range -
18 - 26°; top (1) the diffractogram of the
formulation V2 from Example 23, in the middle (2)
the formulation 2 from Example 23~ and at the
bottom a corresponding amount of crystalline cetyl
palmitate.
