NASHA™ – the MONOGRAPH

Transcription

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™
Text: Bengt Ågerup, Ph.D., Ove Wik, Ph.D.
Illustrations: Ove Wik, Peter Wikstrand
©2008, Q-Med AB, Uppsala, Sweden
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Ta b l e o f cont e nts
1. Introduction
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2. Hyaluronic Acid (HA) 10
3. NASHA™ gels 16
4. Comparison between NASHA™ gels
and other modified hyaluronic acids 22
Recommended reading 24
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1. I ntro d u ction
NASHA™ gels are unique products based on
NASHA technology for production of stabilized
non-animal hyaluronic acid, patented and
developed by Q-Med AB, Uppsala, Sweden.
NASHA gels are products for facial tissue
augmentation and skin rejuvenation (Restylane®),
body contouring (Macrolane™), for treatment of
osteoarthritis in the knee and hip (Durolane®),
for treatment of vesicoureteral reflux (VUR) in
children (Deflux™) and for the treatment of fecal
incontinence (Solesta™).
The manufacture of NASHA gels is based on pure
hyaluronic acid (HA).
Hyaluronic acid is one of nature’s most versatile
and fascinating macromolecules. Since this
polysaccharide was first isolated from bovine
vitreous in the mid-1930s, it has been found in
all tissues in all vertebrates. Thus, hyaluronic acid
is a universal component of the extra-cellular
matrix (ECM), where the molecule has multiple
properties to constitute a matrix that supports
the normal function of cells and tissues.
Hyaluronic acid is a uniform, un-branched linear
polysaccharide with the same simple chemical
structure in all species and tissues. Hyaluronic
acid is also biosynthesized by some bacteria. The
chemical structure of hyaluronic acid is invariable,
i.e. the chemical structure is always the same,
independent of the source. The identical structure
of hyaluronic acid from all sources makes this
polysaccharide an ideal substance for use as a
biomaterial in health and medicine.
Hyaluronic acid
• has a simple chemical structure,
•
•
is identical in all species and in all tissues, and
is hence an ideal biomaterial
Biomaterials are typically macromolecules
extracted from plants or from human or
animal tissues or synthesized to mimic native
biomolecules. The safe use of these materials
must be properly documented in biocompatibility
studies, as these molecules or their contaminants
do differ from their native, human counterparts.
Hyaluronic acid from different sources merely
differs in the length of the molecular chain and,
most importantly, its purity. Sufficiently pure
hyaluronic acid is inherently biocompatible.
However, the presence of impurities, especially
those of animal origin, in hyaluronic acid raw
material may affect the biocompatibility, as
impurities may cause severe adverse reactions
in the human body. The purity of hyaluronic
acid preparations is therefore of the utmost
importance for the safe use of hyaluronic acid
products in humans.
The presence of hyaluronic acid in all tissues,
and the physiological and physical properties of
hyaluronic acid solutions and products have so
far resulted in a number of medical applications:
eye surgery, tissue augmentation, anti-adhesion,
joint disorders in man and horse, purification
and characterization of sperms, etc. Many
other applications have been proposed and are
currently being evaluated. The use of hyaluronic
acid in health care and medicine is limited only
by the lack of effective derivatives. One major
step towards new inventive hyaluronic acid-based
products is the development of NASHA gel.
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2. H y a lu ro n i c A c i d
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Nomenclature
Karl Meyer and his assistant, John Palmer, isolated the
polysaccharide hyaluronic acid (sodium hyaluronate,
hyaluronan) in 1934 from the vitreous of bovine eyes.
They found a substance, which contained two sugar
moieties, one of which was uronic acid. Therefore, to
cite the authors, “we propose, for convenience, the name
‘hyaluronic acid’, from hyaloid (vitreous) + uronic acid”.
Under physiological conditions the polysaccharide
is not present in the acid form, but exists as a salt:
hyaluronate. The most abundant cation in tissues is
sodium, and hyaluronic acid is generally present as
sodium hyaluronate both in tissues and in hyaluronic
acid based products. In agreement with modern
nomenclature of polysaccharides, the term hyaluronan
was proposed in 1986. Pharmacopoeia and regulatory
authorities sometimes use the Latin term Natrii
Hyaluronas. This term should not be confused with
Hyaluronidase, which denotes various enzymes that
degrade hyaluronic acid.
The various terms and their usage in the scientific
literature are shown in the following table:
Name Comment Usage
Hyaluronic acid
Meyer & Palmer,
1934, Medicine
60%
Na-hyaluronate
Salt at neutral pH
Pharmaceutical
10%
Hyaluronan
Balazs et al
Scientific
30%
Natrii hyaluronas
Latin notion
Pharmacopeia
Singular
Chemical structure
Hyaluronic acid has a very simple chemical structure:
a disaccharide unit containing glucuronic acid and
N-acetylglucosamine. These are joined together
forming a uniform, linear polysaccharide molecule as
shown in the following figure:
The number of repeating disaccharide units is denoted
by n. These sugar units are hydrophilic - water loving making hyaluronic acid highly soluble in water.
Hyaluronic acid contains these, and only these, two
sugar units in all tissues and in all species. The identical
hyaluronic acid molecule can also be manufactured
from a non-animal source by modern biotechnological
methods. However, the unique mechanism of
biosynthesis of hyaluronic acid (see Page 13)
demonstrates that hyaluronic acid only contains the
simple disaccharide unit without amino acids, proteins
or other sugar moieties.
The identical chemical structure of hyaluronic acid
– independent of source – is most significant from a
biological point of view. Hyaluronic acid is an ideal
material for use in health care and medicine due to its
inherent biocompatibility.
Molecular weight
Hyaluronic acid is a uniform, linear and un-branched
molecule consisting of multiple identical disaccharide
units. The only difference between hyaluronic acid
preparations is the length of individual molecules.
For example, the molecular size of hyaluronic acid
is often lowered in synovial fluid from patients with
joint disorders. In healthy tissues the molecular weight
of hyaluronic acid is typically in the order of 5 to
10 million. In some tissues or species, especially in
diseased tissues, the molecular weight may be lower: ~1
million. The molecular weight in hyaluronic acid based
products varies from 0.5 to 5 million.
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Molecular length
The length and molecular weight of hyaluronic acid
are determined by the number of disaccharide units
linked together, i.e. the degree of polymerization
denoted by n in the figure above. The length of
hyaluronic acid varies somewhat between different
tissues and species, but there is much larger variation
depending on the condition of the tissue. A
hyaluronic acid molecule with a molecular weight of
10 million contains 25 000 disaccharide units linked
together forming a very long linear chain consisting
of repeating disaccharide units. The hyaluronic acid
molecule in normal tissue with a molecular weight
of 10 million is 1 nm thick and 25 µm long. In
comparison the diameter of a red blood cell is 7.5 µm.
concentration of hyaluronic acid in all tissues is
0,2 mg/g (0.02%). Thus, a human body weighing
60 kg contains about 12 g hyaluronic acid.
Other
µg/ml
Conformation
In solution the very long and thin hyaluronic
acid chain molecules kink and bend and adopt a
conformation of an expanded random coil. These
hyaluronic acid coils are so large that even at a low
concentration of about 0.1% (1 mg/ml) the hyaluronic
acid molecules fill up the whole solution. At higher
concentrations the hyaluronic acid coils intertwine
and entangle, forming a flexible molecular network of
entangled molecules.
This entangled network of hyaluronic acid molecules is
Serum
0,05
Random coils
<1mg/ml
Flexible Molecular
Network
10 mg/ml
able to hold large amounts of water while allowing the
passage of metabolites to and from cells.
Concentration
Hyaluronic acid is an essential component of the
extra-cellular matrix of all tissues. Especially high
concentrations are found in tissues such as the
umbilical cord (4 mg/g), synovial fluid (3-4 mg/g)
and vitreous of the eye (0.1-0.4 mg/g). The average
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Tissue
Hyaluronic acid mg/ml
Synovial fluid
3-4
Vitreous
0,2
Oocyte cumulus
0,5
Extra-cellular space
mg/g
Cartilage
1,2
Skin
0,8
Lung
0,15
Although the highest concentrations of hyaluronic
acid are found in connective tissues, most hyaluronic
acid, 56% (7 g), is found in the skin.
Other 1%
Muscles 8%
Intestines 8%
Skin 56%
Connective
tissues 27%
The normal state of hyaluronic acid in tissues is as a
free polymer. However, in some tissues such as the
cartilage and tendons hyaluronic acid can be bound to
large glycoprotein structures (proteoglycans) or in other
tissues to specific cell receptors (e.g. CD 44).
Metabolism
The metabolism – the biosynthesis and the catabolism
– of hyaluronic acid is in many ways unique. The
biosynthesis occurs via an enzyme complex within the
cellular membrane, and the removal and degradation of
hyaluronic acid is receptor binding mediated followed
by intracellular degradation. This process is very fast and
efficient.
Biosynthesis
The unique cell ‘machinery’ that synthesizes
hyaluronic acid has been elucidated during the last
decades. Biomolecules – both intracellular and extracellular components – are synthesized within the cell.
Vertebrate polysaccharides are generally synthesized
onto a protein core that works as a primer. The
enzyme complex producing hyaluronic acid is not
situated within the cell but is maintained within the
cell membrane.
The two basic sugar units are added onto the growing
hyaluronic acid chain from the cell interior, and the
hyaluronic acid product is released directly into the
surrounding extra-cellular matrix (ECM).
Many different cells have the capacity to produce
hyaluronic acid, e.g. fibroblasts, synovial cells,
endothelial cells, smooth muscle cells, adventitial
cells and oocytes. The same synthase that produce
invariant hyaluronic acid has been identified in a
number of species: humans, mice, chickens, frogs,
and zebra fish. These facts confirm the concept of a
uniform chemical structure of hyaluronic acid within
the animal kingdom.
Catabolism
The overall turnover rate of hyaluronic acid is very fast
compared to that of other extra-cellular components
such as collagen. The half-life of hyaluronic acid in
most tissues ranges from 0.5 to a few days. In skin the
half-life is <24 hours. The daily turnover of hyaluronic
acid is in the order of one-third of the total body
content at a rate similar to that of albumin. In an
adult body (ca. 60 kg), about 3-4 grams of hyaluronic
acid are thus catabolized each day.
The very fast turnover rate of hyaluronic acid takes
place in a series of steps as outlined below. First, the
large hyaluronic acid molecules move at a remarkable
speed by means of a reptation mechanism. The
flexible molecules disentangle and move out of the
molecular network with a snake-like motion. Cell
receptors bind the free hyaluronic acid molecules,
which are engulfed by the cells. Intracellular enzymes
in the lysosomes subsequently degrade the hyaluronic
acid to its basic constituents.
Residence time and molecular
weight
The residence time of hyaluronic acid in tissues is only
slightly dependent on molecular weight. Endogenous
and exogenous hyaluronic acid generally has a
molecular weight ranging from 1 to 10 million. The
turnover of hyaluronic acid in rabbit knee joints as a
function of molecular weight is shown below. Despite
the more than 10-fold difference in molecular weight
of the implanted hyaluronic acid samples, there is
only a 30% difference in half-life time.
Hyaluronic acid in most commercial products has
a molecular weight of 1 million. There are some
products with a molecular weight of 5 million and
a few modified products with a molecular weight
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Hyaluronic acid
Exogenous
Molecular
weight
100 000
Half-life time
(hours)
10
Exogenous
6 000 000
13
Endogenous
13 000 000
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From: Brown, T.J. et al. Exp. Physiol. 76(1991): 125-34.
of 10 million. The residence time of hyaluronic
acids implanted in different tissues will be affected
by the molecular weight of the hyaluronic acid in
approximately the same way as the residence time in
joints as shown above. Inflammatory processes will
degrade the hyaluronic acid almost instantaneously.
For the majority of medical applications of hyaluronic
acid a residence time in the order of weeks or months
is necessary to accomplish the desired effect of the
implanted hyaluronic acid. It is evident that hyaluronic
acid must be modified in order to obtain a product
with a reasonable duration.
Stabilization VS cross-linkage
The most common way of prolonging the residence
time of hyaluronic acid in tissue is by cross-linkage.
Cross-linked HA-products can be chemically modified
up to 50%. Because hyaluronic acid is a natural
polymer a high level of cross-linkage will render the
polymer from being natural to being foreign. Hence a
foreign body reaction will take place.
Stabilization is the process by which the natural
hyaluronic acid polymer is chemically modified to the
lowest possible degree. The biocompatibility of the
resulting gel is thereby maintained and a long-lasting
effect is achieved.
The NASHA™ gel is further described in Chapter 3.
Physiological function
Hyaluronic acid is an important component of the
extra-cellular matrix (ECM) and has an important
role in the maintenance of the proper structure and
function of tissues by:
• Creating volume
• Lubricating tissues
• Affecting cell integrity, mobility and proliferation
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The physiological function of hyaluronic acid is based
on the very large size and hydrodynamic volume of
the hydrophilic (water-retaining) molecular network.
In the extra-cellular matrix (ECM), the hyaluronic
acid network has the capacity to hold large amounts
of water. Elevated levels of extra-cellular hyaluronic
acid accompany processes that require cell movement
and tissue reorganization. That is, when cells need
space for motility and separation these functions
are performed in a hyaluronic acid medium. The
hyaluronic acid network assists in cell differentiation,
cell migration, tissue morphogenesis, embryogenesis
and wound repair. Tissues involved in movement
such as joints are lubricated by hyaluronic acid. Such
effects are dependent on the rheological status of the
fluid. The most important property of the rheological
performance of hyaluronic acid is mediated through
its molecular weight. The high viscosity and elasticity
of hyaluronic acid solutions will create thick layers
of unstirred fluid that will protect the tissues under
movement.
Biocompatibility
In general, biomolecules synthesized by different
species differ in chemical composition. The difference
in e.g. the amino acid composition of proteins and
sugar components of glycoproteins makes these
molecules foreign to another species or individual. The
body responds in various ways when such different
molecules are encountered: immunological reactions
or rejection of organs transplanted. In contrast to
other biomolecules hyaluronic acid is independent
of source as the chemical structure is invariant. All
cells that synthesize hyaluronic acid produce the same
compound. This also applies to the hyaluronic acid
produced by some bacteria, which have taken the
enzymatic machinery for biosynthesis of hyaluronic
acid from vertebrates. The bacteria with a protective
coat of hyaluronic acid will not as easily be recognized
as foreign by the body defence systems and the
inflammatory reaction will be greatly reduced.
Manufacturing
Hyaluronic acid may either be obtained by
extraction from tissues or produced by using modern
biotechnological methods. The extensive entanglement
of hyaluronic acid with other components in tissues
complicates its isolation and purification from animal
sources. In practice it is inevitable that hyaluronic acid
isolated from tissues will contain impurities. With
regard to the type of impurity and the amount of
impurities, there are large and significant differences
between different hyaluronic acid preparations. The
purity of hyaluronic acid depends on the choice of
raw material, method of manufacturing and molecular
weight of the isolated hyaluronic acid.
Tissue extraction
Tissues containing large amounts of hyaluronic acid
have been utilized as raw material. Rooster combs has
been the major source for tissue-derived hyaluronic
acid.
Biotechnology
Cells capable of producing hyaluronic acid are found
not only in animal tissues, but also interestingly,
some bacteria have taken the unique enzymes that
synthesize hyaluronic acid. These cells can be utilized
for production of hyaluronic acid by using modern
biotechnological methods. The cells are grown in
a medium containing water and nutrients. The
hyaluronic acid synthesized within the cell membrane
is excreted into the medium for easy access and
purification. Provided that the integrity of the cells is
maintained during manufacturing, the hyaluronic acid
produced will contain only minute and insignificant
amounts of other biomolecules.
Biotechnology versus Tissue extraction
Tissues are, from many aspects, a complicated starting
material for the manufacture of highly purified
hyaluronic acid. Isolation of hyaluronic acid from a
tissue necessitates the mincing of tissues. Therefore,
the initial raw material is a complex mixture of
tissue components and contaminant products. The
complete isolation of hyaluronic acid from minced
tissues is essentially impossible to accomplish due to
the low concentration (ca. 0.5%) of hyaluronic acid.
The very high molecular weight (appr. 10 million)
hyaluronic acid is extensively intermingled with other
biomolecules and cells, and the final product will
contain significant amounts of impurities.
Tissue extractions contain a mixture of various kinds
of contaminants in different proportions: exogenous
from bacteria and fungi as well as endogenous from
healthy and infected cells. On the other hand, the
simple isolation of hyaluronic acid from a bacterial
fermentation process by filtration yields a pure extract
with well-known and reproducible contaminant
profile. It is obvious that the isolation of hyaluronic
acid from a simple medium is much easier, safer and
more reproducible than the isolation of hyaluronic acid
from minced tissues.
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3. n a s h a ™ g e l s
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The development of the NASHA™ technology was
based on two basic considerations not yet seen in the
business:
The minor modification needed to obtain the stabilized
NASHA gel is presented in the following figures:
• Pure hyaluronic acid
• Mild chemical stabilization to obtain the optimal
performance in the various clinical applications
without starting a foreign body reaction.
The outcome was a gel with properties that combine
a long residence time in the body and essentially the
absence of foreign body reactions, resulting from the
very low protein level and the low degree of chemical
modification of the hyaluronic acid raw material.
Starting material
The hyaluronic acid raw material used in the production
of NASHA gels is biosynthesized from a non-animal
source using biotechnological methods. The molecular
weight of the hyaluronic acid is ~1 million. Higher
molecular weights are not needed as the hyaluronic acid
is stabilized.
Stabilization and manufacture
The manufacture of NASHA gels is performed under
controlled conditions at Q-Med AB, Uppsala, Sweden.
The manufacturing process includes the stabilization of
hyaluronic acid. The stabilized material is a continuous
3-dimensional molecular network – i.e. a gel of any
shape and form. In some applications gel particles
of defined sizes are produced. This unique NASHA
technology, which can produce a defined polymer with a
physical form that matches the intended use, is nowhere
else to be found.
The products are steam-sterilized in order to achieve
maximum safety. The NASHA gels have a sterility
assurance level (SAL) of 10-6. This method is superior
to aseptic manufacturing, and results in a product
where the probability of finding a syringe containing a
microorganism is less than 1 in 1 million units.
The stabilization process is essential in order to improve
the residence time in the body following injection
from a few days to many months. To maintain the
ultimate tolerance of native hyaluronic acid only a slight
stabilization of the hyaluronic acid network is carried
out.
A hyaluronic acid molecule with the flexible
molecular network entangles with its neighbours. This
entanglement strongly hampers the movement of the
molecules sideways. However, individual molecules
are capable of moving within the flexible molecular
network at a remarkable speed by means of a snake-like
movement called reptation.
In NASHA gels, the hyaluronic acid molecules are
stabilized to a minor degree (<1%). Due to the high
molecular weight of the starting material (1 million)
only a minor extent of stabilization is needed to obtain a
few permanent linkages that join all the hyaluronic acid
molecules in the solution, thus forming a continuous
gel. Therefore, a very low amount of stabilizer is needed.
Molecular weight
The molecular weight of hyaluronic acid in various
commercial products varies between 1 and 10 million.
In NASHA gels the hyaluronic acid molecules are
stabilized by linking the molecules together. In
hyaluronic acid solutions the molecules form an
entangled molecular network where the molecules can
move freely, whereas the stabilized molecules form a
stable 3-dimensional molecular network, a so-called
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gel. From a scientific point of view it is not common
practice to calculate the molecular weight of a gel.
Nevertheless, it may be appropriate to do so in order
to demonstrate the very large difference between nonstabilized and stabilized hyaluronic acid, such as that
in NASHA™ gels. Each NASHA gel particle contains
billions of stabilized hyaluronic acid molecules. As these
molecules with a molecular weight of 1 million are
bound together, we find that the molecular weight of a
NASHA gel particle is higher than 100 billion.
Purity
The hyaluronic acid raw material used in the
manufacture of NASHA gels is produced from a nonanimal source by biotechnological methods, in order
to obtain a product of high purity. The amounts of
impurities are minimized by preserving the integrity
of the hyaluronic acid producing cells. Subsequent
isolation of hyaluronic acid aims at reducing the
amount of impurities instead of maintaining as high a
molecular weight as possible. The presence in NASHA
gels of potentially harmful components such as viruses,
proteins and endotoxins in general, and those of animal
origin in particular, is therefore essentially excluded.
Biocompatibility
The concept ‘Biocompatibility’ was originally defined
as “the total absence of interaction between the material
and the tissues”. This definition has been modified
to read: “the ability of a material to perform with an
appropriate host response in a specific application”
Hyaluronic acid in itself is fully biocompatible, as
described above. The question of the biocompatibility
of hyaluronic acid products is therefore related to the
amount and type of impurities present in the product as
well as the degree of modification.
Nevertheless, the biocompatibility of NASHA gels has
been tested in accordance with the guidelines of the ISO
(International Organization for Standardization) 10993
standard on “Biological Evaluation of Medical Devices”.
These tests have shown that NASHA gels have a very
good safety profile.
NASHA gels:
•do not cause any local or systemic toxic effects
•are not genotoxic
•are not sensitizing or irritating 18
Residence time of NASHA GELS
As discussed above the turnover of endogenous
hyaluronic acid is very fast and efficient. In most
tissues the half-life varies from half a day to a few days.
Exogenous hyaluronic acid implanted into a tissue will
similarly disappear within this short time. The residence
time in the body may be slightly modified by changing
the molecular size or concentration of hyaluronic acid,
or by modifying the method of application. However,
increase of the hyaluronic acid molecular weight will
increase the residence time only slightly, by a factor <2.
Hyaluronic acid molecules within the extra-cellular
matrix (ECM) are able to move towards cells, where the
molecules bind to the cellular membrane for subsequent
pinocytosis. The most abundant removal is carried out
by lymphatic uptake, partial depolymerization and
removal to the blood stream. Blood is then effectively
cleared from hyaluronic acid by uptake and hepatic
degradation to carbon dioxide and water. When
NASHA gel is implanted into a tissue a prerequisite
for removal of the stabilized hyaluronic acid is the
degradation in situ of the 3-dimensional hyaluronic acid
gel matrix.
In healthy tissue the extra-cellular capacity to degrade
hyaluronic acid is very low. The most probable means
of degradation is by the action of free radicals. These
are ubiquitously present in very low concentrations
in normal tissue. However, the capacity of free
radicals to break down hyaluronic acid molecules is
well documented. The very slow degradation of the
stabilized HA gel matrix results in the slow release of
free hyaluronic acid chains, which are thus catabolized
by the same mechanism that degrade endogenous
hyaluronic acid, as described above. As a consequence
of the mild stabilization of hyaluronic acid in NASHA™
gels the residence time in e.g. the skin has been
increased from a few days to several months, sometimes
even up to one year.1, 2, 3
Residence time
The residence time of NASHA gel is dependent on the
tissue of implantation, the concentration of stabilized
hyaluronic acid and the existence of inflammatory
reactions in the area. Hence a careful tissue match is
essential. Too much of chemical modification of the
hyaluronic acid raw material will render the gel foreign
to the host. As a consequence, inflammatory reactions
and subsequent enhanced degradation of the gel will
follow.
Isovolemic degradation
The NASHA gel will be subject to isovolemic
degradation. That is to say, the gel will stay
approximately the same size and shape as injected
despite continuous degradation and thinning out. This
is so because the amount of stabilized hyaluronic acid
in NASHA gels is about 5 times the amount needed to
maintain its volume. The surplus material is merely used
to make the gel to last longer.
be thick or thin, dense or loose as well as containing
big or small gel particles. For the purpose of tissue
augmentation, the size of the gel particles should match
the density of the tissue. For facial augmentation e.g.
several products with different size of the gel particles
have been developed by Q-Med, where each product is
perfectly designed for the specific tissue layer.
Clinical uses of NASHA gels Products on the market
The clinical uses of NASHA gel are not limited by
its physical characteristics or degree of purity. Many
esthetic and medical intended uses could thus be
considered. Q-Med has designed its products on the
basis of patient’s needs and the clinical advantages
achieved through the uniqueness of the products for
each specific indication.
For esthetic use, facial soft tissue augmentation, the
gel does not just predictably augment the tissue to full
esthetic satisfaction but also adds stabilized hyaluronic
acid to the extra-cellular environment. So far, more
than ten million treatments have been performed with
Restylane®. The products in the Restylane family are
intended for facial soft tissue augmentation such as
filling folds and lines, contouring and creating volume,
as well as for skin rejuvenation.
Gels of any shape and form
Thanks to the unique and patented NASHA technology,
the gel can be manufactured to almost any shape and
form. Depending on the clinical demand, the gels can
NASHA™ gel is isovolemically degraded, i.e. initially, the amount of stabilized hyaluronic acid is larger
than the amount needed to maintain its volume.
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Macrolane™ VRF products are NASHA™ gels for
volume restoration and contouring of body surfaces.
Thanks to the unique and patented NASHA technology,
and the purity of the gel, Macrolane can be injected in
large volumes. Macrolane is injected subcutaneously
and/or subglandularly and is available in two
formulations, or volume restoration factors, Macrolane
VRF20 and Macrolane VRF30. Macrolane gels allow
you to fill large areas at deep tissue level with predictable
and immediate results.
Durolane® is a product intended to diminish pain and
improve mobility among patients suffering of mild to
moderate knee or hip osteoarthritis (OA).
The body’s own hyaluronic acid constitutes a natural
part of the synovial fluid and acts in the joints both as
a lubricant of cartilage and ligaments and as a shock
absorber. It is known that the synovial fluid in joints
affected by osteoarthritis has a lower viscosity and
elasticity than in healthy joints. Injections of hyaluronic
acid in the joint to restore the viscosity and elasticity can
diminish the pain and improve the mobility of the joint.
The stabilized hyaluronic acid used in Durolane remains
in the joint for a prolonged time, thereby eliminating
the need for multiple weekly injections normally used
for other products.
NASHA gels for urological indications have also been
developed, resulting in a product (Deflux®) for the
treatment of VUR (Vesicoureteral Reflux) in young
children. The stabilized hyaluronic acid acts mainly
as carriers of dextranomer beads that are gradually
surrounded by host connective tissue. Once the
implant is in place, the stabilized hyaluronic acid
gel is reabsorbed. Deflux is intended to augment the
urinary bladder wall at the orifice of the ureter to
form a ventilum that prevents urine leaking back and
consequent kidney infections.
Solesta™ is another NASHA product where stabilized
hyaluronic acid is used as carrier of dextranomer beads.
It is intended to reduce the rectal sphincter area in
order to assist in maintaining faecal continence. Fecal
incontinence, involuntary passage of fecal material
through the anal canal, is a major problem for around
one in 50 adults. It has a devastating effect on quality of
life and psychological well-being. There is a high degree
of association between fecal and urinary incontinence.
Both conditions are often the result of child birth
complications. Despite the high frequency of fecal
incontinence very few seek help and instead suffer in
silence.
Clinical studies
NASHA gels are continuously being used in
international clinical trials for a number of indications.
Many trials are carried out in accordance with FDA
approved protocols for the purpose of documenting
products for sale on the US market.
Esthetic products
Several clinical studies have been performed in order to
evaluate the safety and efficacy of Restylane® products.
The safety profile of this product family is excellent.
Reports of inflammatory reactions in treated patients
are rare. The majority of reactions are of mild intensity
and transient. Comparative trials have been carried
out with FDA approved protocols for the purpose of
documenting products for sale on the US market. The
FDA approved Restylane in December 2003 as being
the first dermal filler based on hyaluronic acid. In May
2007 Restylane Perlane™ was approved by FDA.
In a recently published study carried out on patients
with photodamaged skin, an increase in collagen
production was observed after injecting NASHA™ gel
into the dermis (Wang et al, 2007).
The rejuvenating effect of a NASHA gel on aged facial
skin has also been studied. The result showed that
skin elasticity and skin surface roughness improved
significantly (Kerscher et al, 2008).
The potential of Macrolane ™ gels for body contouring
as well as for correction of non-facial indentations
resulting from liposuction, surgery or trauma has been
evaluated in clinical studies since 2002, aiming at
establishing the safety, efficacy and tolerability of the
product for the recommended intended uses. In a study
20
on the use of Macrolane gels for body contouring, very
promising results in the correction of concave body
deformities resulting after liposuction were obtained.
Macrolane gel was injected into the subcutaneous fatty
tissue and/or supraperiostally and spread into the area
to be augmented. Both patients and physicians were
satisfied with the results, as evaluated using a Global
Esthetic Improvement Scale (GEIS). There were no
serious adverse events (AE) reported and the majority
of the treatment-related AE were mild/moderate in
intensity and transient in nature. Macrolane VRF gels
for volume restoration and contouring of body surfaces
were CE marked in September 2007. Further, a pilot
study is ongoing to evaluate the safety and efficacy of
Macrolane gels for the augmentation of the female
breast. Twenty patients have been included in the study.
The follow-up period of the study is two years.
gel implants are non-animal and slowly degradable thus
giving a prolonged residence time.
Hospital Specialist Products
Osteoarthritis
Clinical trials have demonstrated the efficacy and
safety of Durolane®. One injection of Durolane is well
tolerated and may provide significant improvements
in the joints decreasing pain for up to 6 months
after treatment. Most of the available data for
Durolane relate to osteoarthritis (OA) of the knee, as
viscosupplementation is most commonly used for this
condition. The potential use of Durolane for OA in the
hip have also been investigated, and in 2004 Durolane
was granted a wider indication including hip OA in
Europe.
Fecal Incontinence
Early experience and clinical studies with Solesta™ show
a reduction in incontinence episodes of approximately
50%. This improvement, compared to more invasive
and expensive surgery, has a major positive impact on
patients’ quality of life.
Endoscopic treatment with Deflux® has provided
successful outcomes worldwide for more than twelve
years. Deflux has a well-documented safety record
with more than 50 000 children successfully treated
with no reports of persistent adverse events. Longterm success with Deflux has been demonstrated in
several studies with up to twelve years of follow-up.
Numerous publications provide positive evidence for
Deflux in areas such as efficacy, safety, duration, success
also in complicated cases as well as patient and parent
preference for Deflux over other treatment options.
Recent publications show that Deflux not only treats
VUR but also reduces the incidence of urinary tract
infections, a potential cause of renal scarring.
For patients with fecal incontinence Solesta is injected
under direct vision in the sub-mucosal layer of the
anal canal, with the aim to improve the anal sphincter
function. Anesthesia and antibiotic prophylactics are
not required. If no bleeding or other treatment related
symptoms appear the patient may be allowed to leave
the clinic within 60 minutes after the procedure.
Vesicoureteral Reflux
Clinical experience over the last two decades has
demonstrated that the endoscopic correction of
primary vesicoureteral reflux (VUR) is both possible
and effective. However, the substances used in Europe
as well as the US have been permanent or quickly
degradable animal implants. The NASHA dextronomer
21
4. COM PA R ISON BE T W E E N
NA SH A™ GE L S A N D OT H E R
MODI FI E D H YA LU RON IC ACI DS
22
By far the most popular technique to convert natural
hyaluronic acid into long lasting forms is to cross-link
the polymer. It is not unusual with a level of crosslinkage that exceeds 10% and often reaches even
50%. In doing so, the material is changed from being
natural with physiological routes of degradation, to
unnatural with limited ways of being eliminated from
the body. The highly praised biocompatibility of natural
hyaluronic acid will thus be substantially reduced in the
highly cross-linked material so that the residence time in
tissues is in fact shortened rather than prolonged due to
inflammatory counter reactions.
It is thus questionable to consider highly cross-linked
hyaluronic acid as hyaluronic acid, since such a substance
would not be recognized or fit to cellular receptors nor is
metabolized through the normal physiological pathways.
STABILIZATION
With NASHA™ technology a minimum degree
of binding between neighbouring hyaluronic acid
molecules is obtained. This modification results in an
immobilization of the hyaluronic acid molecules.
The two basic aspects of the NASHA technology are:
• Minimization of impurities
The HA used in the manufacturing process of
NASHA gel implants is produced by bacterial cells.
By using bacteria as a source for HA the risk of having
products contaminated with, for example, viruses
or proteins from animal sources has been abrogated.
In addition, the carefully controlled fermentation
process, by which the HA is produced, will minimize
the presence of potentially harmful components, such
as proteins, endotoxins and other impurities. The
HA thus obtained is characterized by a high degree of
purity.
• Minimal modification
In order to obtain a product with a prolonged
residence time, it is sufficient to stabilize each
molecule with its neighbours, i.e. retain the natural
network of the HA-chains. In NASHA gels, a very
low degree of stabilization (<1%) has proven to
be sufficient to obtain a product with the desired
properties.
Thus, the NASHA gel is a stabilized hyaluronic acid
molecular network of non-animal origin where the
hyaluronic acid has been subjected to a minimum
degree of chemical modification to create products with
the desired properties and duration of effect.
23
RECOMMENDED READING
1. Lindqvist C, Tveten S, Bondevik BE, et al: A randomized, evaluator-blind, multicenter
comparison of the efficacy and tolerability of Perlane® versus Zyplast® in the correction of
nasolabial folds. Plast Reconstr Surg 2005; 115(1):282-9
2. Narins RS, Brandt F, Leyden J, et al: A randomized, double-blind multicenter comparison of
the efficacy and tolerability of Restylane® versus Zyplast® for the correction of nasolabial folds.
Dermatol Surgery 2003; 29(6):588-95
3. Olenius M: The first clinical study using a new biodegradable implant for treatment of lips,
wrinkles and folds. Aesthetic Plast Surg 1998; 22:97-101.
4.
Åkermark C, Berg P, Björkman A, et al: Non-animal stabilised hyaluronic acid in the treatment
of osteoarthritis of the knee - a tolerability study. Clin Drug Invest 2002; 22:157-66.
5. Altman RD, Åkermark C, Beaulieu AD, et al: Efficacy and safety of a single intra-articular
injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of
the knee. Osteoarthritis Cartilage 2004; 12:642-9.
6. Berg P, Olsson U: Intra-articular injection of non-animal stabilised hyaluronic acid (NASHA) for
osteoarthritis of the hip: a pilot study. Clin Exp Rheumatol 2004; 22:300-6.
7.Läckgren G, Wahlin N, Stenberg A: Endoscopic treatment of children with vesico-ureteric
reflux. Acta Paediatr 1999; 88 (Suppl, 88):62-71
24
8. Stenberg A, Läckgren G: A new bioimplant for the endoscopic treatment of vesicourethral reflux:
experimental and short-term clinical results. J Urol 1995; 154:800-3
9. Kirsch AJ, Perez-Brayfield M, Smith EA, et al: The modified STING procedure to correct
vesicourethral reflux: improved results with submucosal implantation within the intramural
ureter. J Urol 2004; 171:2413-6
10.
Stenberg AM, Larsson G, Johnson P: Urethral injection for stress urinary incontinence: longterm results with dextranomer/hyaluronic acid copolymer. Int Urogynecol J Pelvic Floor Dysfunct
2003; 14(4):335-338
11. van Kerrebroeck P, ter Meulen F, Larsson G et al: Efficacy and safety of a novel system (NASHA/
Dx copolymer using the IMPLACER device) for treatment of stress urinary incontinence.
Urology 2004; 64(2):276-81
12. Chapple CR, Haab F, Cervigni M, Dannecker C, Fianu-Jonasson A, Sultan AH: An open,
multicentre study of NASHA/Dx Gel (Zuidex) for the treatment of stress urinary incontinence
Eur Urol 2005 Sep;48(3):488-94
13. Wang F, Garza LA, Kang S, Varani J, Orringer JS, Fisher GJ, Voorhes JJ: In vivo stimulation of
de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in
photodamaged skin. Arch Dermatol 2007; 143:155-163.
14. Kerscher M, Reuther T, Bayrhammer J, Krüger: Study of the effects of stabilized non-animal
hyaluronic acid on the biophysical properties of the skin, Dermatol Surg 2008; 34:1-7
15. The Restylane® publications booklet, 6th ed., Q-Med AB, 2007.
25
26
27
15-10040-05. NASHA, Restylane, Macrolane, Deflux and Solesta are trademarks owned by Q-Med AB.
28
Seminariegatan 21 • SE-752 28 Uppsala • Sweden
Phone: +46(0)18-474 90 00 • Fax: +46(0)18-474 90 01 • e-mail: [email protected] • website: www.q-med.com

NASHA™ – the MONOGRAPH

Transcription

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