CA2561685C

CA2561685C - Method of soft tissue augmentation

Info

Publication number: CA2561685C
Application number: CA2561685A
Authority: CA
Inventors: Bengt Agerup
Original assignee: Q Med AB
Current assignee: Q Med AB
Priority date: 2004-04-08
Filing date: 2005-04-07
Publication date: 2013-03-12
Anticipated expiration: 2025-04-07
Also published as: KR20070017172A; AU2005231674A1; WO2005097218A2; RU2006139141A; JP2007532173A; US20050226936A1; JP5074182B2; US20140147479A1; JP2012179467A; CN1950039B; EP1734894B1; BRPI0509678A; AU2005231674B2; CA2561685A1; CN101897993A; EP1734894A2; EP1734894B2; US20230211051A1; ES2599329T3; US20200030494A1

Abstract

Particles according to the invention are made of a viscoelastic medium, are injectable gel particles, and have a size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm. The particles are useful in a soft tissue augmentation implant. The implant comprises particles of a viscoelastic medium, wherein a major volume of the particles are injectable gel particles according to the invention. The implant is useful in a method of soft tissue augmentation in a mammal, including man, comprising subepidermal administration at a site in said mammal where soft tissue augmentation is desirable, of an implant according to the invention.

Description

METHOD OF SOFT TISSUE AUGMENTATION

FIELD OF THE INVENTION
The present invention relates to the fields of esthetics and plastic surgery, including cosmetic and reconstructive surgery. More specifically, the invention is concerned with a method of soft tissue augmentation in a mammal, including man. Moreover, the invention is directed to use of particles of a viscoelastic medium for the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, including man. The invention is also concerned with particles of a viscoelastic medium, production thereof, and use thereof in an implant.

BACKGROUND TO THE INVENTION
An implant material that is useful for soft-tissue augmentation should ideally be capable of providing adequate and sustained aesthetic and/or therapeutic correction without migration and displacement; natural looking and non-palpable; easy to administer and, if necessary, remove; non-immunogenic; and devoid of chronic inflammatory reactions (Krauss MC, Semin Cutan Med Surg 1999; 18: 119-128). As a soft-tissue augmentation material, hyaluronic acid (a naturally occurring polysaccharide).has low immunogenic potential, being chemically homogenous across all species and tissues' (Larsen NE et al., J Biomed Mater Res 1993; 27: 1129-1134). Stabilization (or cross-linking) of the hyaluronic acid molecule improves its resistance to enzymatic degradation without compromising its biocompatibility, while the use of a non-animal source reduces the likelihood of antigenic contamination and subsequent hypersensitivity reactions (Friedman et al., Dermatol Surg 2002; 28: 491-4).

Non-animal stabilized hyaluronic acid (NASHA), US
patent 5,827,937, may be produced from a highly purified hyaluronic acid preparation obtained by bacterial fermentation. Various NASHA preparations of different particle size (Restylane Perlane, Restylane , Restylane Fine Lines and Restylane Touch, all from Q-Med AB, Uppsala, Sweden) have been developed as dermal fillers for facial soft-tissue augmentation. Clinical studies indicate that known NASHA gels are effective in augmenting lips (Bousquet M-T and Agerup B, Oper Techniques Ocuplast Orbit Reconstruct Surg 1999; 2: 172-176) and correcting facial wrinkles and folds (Olenius M.
Aesth Plast Surg 1998; 22: 97-101; Duranti F et al., Dermatol Surg 1998; 24:1317-25; Narins RS et al., Dermatol Surg 2003; 29: 588-95; Carruthers J and Carruthers A, Dermatol Surg 2003; 29: 802-9), and that they offer a more durable aesthetic improvement than bovine collagen or hylan B. The extensive clinical experience gained from their intradermal use in some 1.5 million facial cosmetic procedures confirms their safety.
It is recommended that RESTYLANE Touch (-500,000 particles/ml, mean particle size 0.2 mm) should be injected in the upper part of the dermis; RESTYLANE
(-100,000 particles/ml, mean particle size approximately 0.4 mm) should be injected in the mid-part of the dermis;
and RESTYLANE Perlane (-10,000 particles/ml, mean particle size approximately 0.8 mm) should be injected in the deep layer of the dermis and/or the surface layer of the subcutis.
Some known soft-tissue augmentation treatments involving implantation of viscoelastic materials occasionally suffer from the drawback that the implant, or part thereof, migrates away from the desired site of treatment. Another problem with some known tissue augmentation treatments involving implantation of viscoelastic materials is that the implant is displaced from the desired site of treatment. Implant migration and displacement are disadvantageous for the patient, since they may impair-the cosmetic and/or therapeutic outcome of the treatment and may impede removal of the implant, if this is desired.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an implantation material suitable for soft tissue augmentation which overcomes drawbacks with known implantation materials. It is also an object of the.
present invention to provide a method of producing such an implantation material.
It is another object to provide an implant suitable for soft tissue augmentation comprising such an implantation material which overcomes drawbacks with known implants. It is a further object of the present invention to provide an implant suitable for soft tissue augmentation comprising such an implantation material which is readily removable if desired.
It is another object of the present invention to provide a method of soft tissue. augmentation: in a mammal, including man, which overcomes drawbacks with known methods. It is one object of the present invention to provide a method of soft tissue augmentation in a mammal, including man, comprising subepidermal administration of an implant, which avoids or diminishes undesired migration of the implant from the desired site of implantation. It Lis one object of the present invent ion to provide a method of soft tissue augmentation in a-mammal, including man, comprising subepidermal administration of an implant, which avoids or diminishes displacement of the implant from the desired site of implantation.
It is also an object of the present invention to provide use of a v-iscoelastic medium for the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, including man.

For these and other objects that will be evident from the following disclosure, the present invention provides particles of a viscoelastic medium, which are injectable gel particles having a size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm.

According to another aspect of the present invention, there is provided particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, which particles are injectable gel particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm.

According to still another aspect of the present invention, there is provided a method of producing injectable gel particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, comprising the steps of: (i) manufacturing a gel with a desired concentration of said viscoelastic medium; and (ii) mechanically disrupting said gel into gel particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm.

According to yet another aspect of the present invention, there is provided a soft tissue augmentation implant comprising particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, wherein more than 50% (v/v) of said particles are injectable gel particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm.

According to a further aspect of the present invention, there is provided use of an implant comprising injectable gel particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, more than 50% (v/v) of said particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm, for soft 4a tissue augmentation in a mammal, wherein the implant is for subepidermal administration at a site in said mammal where soft tissue augmentation is desirable.

According to yet a further aspect of the present invention, there is provided use of injectable gel particles of a viscoelastic medium as described herein, more than 50% (v/v) of said particles having an average size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm, for the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, wherein said medicament is for subepidermal administration at a site in said mammal where therapeutic soft tissue augmentation is desirable.

The invention is based on the finding that subepidermal administration of an implant comprising gel particles made of a viscoelastic medium which are considerably larger than previously used in implants made of viscoelastic media are useful in avoiding migration and/or displacement of the implant, or part thereof, from the desired site of soft tissue augmentation. Moreover, the limited displacement of the implant in combination with the considerable particle size facilitates easy removal of the implant, if desired.

In certain preferred particles according to the invention, said size is in the range of from 1 to 2.5 mm. In other preferred particles according to the invention, said size is in the range of from 2.5 to 5 mm.

In preferred particles according the invention, said viscoelastic medium is selected from the group consisting of polysaccharides and derivatives thereof. In more preferred particles according the invention, said viscoelastic medium is selected from stabilized glycosaminoglycans and derivatives thereof. In certain preferred particles according the invention, said viscoelastic medium is selected from the group consisting of stabilized hyaluronic acid, stabilized chondroitin sulfate, stabilized heparin, and derivatives thereof.

4b In preferred particles according the invention, said viscoelastic medium is selected from the group consisting of cross-linked hyaluronic acid and derivatives thereof.

In particularly preferred particles according the invention, the concentration of said viscoelastic medium in said gel particles, when subjected to a physiological salt solution, is in the range of from 5 to 100 mg/ml.
Preferred particles according to the invention are injectable through a 20 gauge or larger needle by 5 application of a pressure of 35-50 N.
According to another aspect of the invention, there is provided a method of producing injectable gel particles of a viscoelastic medium, comprising the steps of: (i) manufacturing a gel with a desired concentration of said viscoelastic medium; and (ii) mechanically disrupting said gel into gel particles having a size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm.
According yet another aspect of the invention, there is provided a soft tissue augmentation implant comprising particles of a viscoelastic medium, wherein a major volume of said particles are injectable gel particles having a size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm. In preferred embodiments of the implant, said size is in the range of from 1 to 2.5 mm. In other preferred embodiments of the implant, said size is in the range of from 2.5 to 5 mm.
According to one aspect of the invention, there is provided a method of soft tissue augmentation in a mammal, including man, compriB ing subepidermal administration at a site in said mammal where soft tissue augmentation is desirable, of an implant comprising injectable gel particles of a viscoelastic medium, a major volume of said particles having a size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm. In preferred embodiments of the method according to the invention, said administration is selected from the group consisting of subcutaneous administration, submuscular administration and supraperiostal administration-In certain methods according to the invention; said size is in the range of from L to 2.5 mm. In a preferred embodiment of this method, said site of soft tissue augmentation is selected from facial tissue and other tissues covered by exposed skin. In other methods according to the invention, said size is in the range of from 2.5 to 5 mm.
In preferred methods according to the invention, said administration is a selected from the group consisting of single administration and multiple-layer administration.
According to another aspect of the invention, there is provided injectable gel particles according to the invention for use as a medicament. There is also provided an injectable soft tissue augmentation implant comprising injectable gel particles according to the invention for use as a medicament.
According to yet another aspect of the invention, there is provided use of injectable gel particles of a viscoelastic medium according to the invention, a major volume of said particles having an average size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm, for the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, including man, wherein said medicament is suitable for subepidermal administration according to the invention at a site in said mammal where therapeutic soft tissue augmentation is desirable.

DETAILED DESCRIPTION OF THE L NVENTION
According to one aspect of the invention, there,is provided particles of a viscc>elastic medium, which are injectable gel particles having a size, when subjected to a physiological salt solution, in the range of from 1 to 5' mm. The particles are useful in a soft- tissue augmentation implant comprising particles of a viscoelastic medium, wherein a major volume of said particles are injectable gel particles according to the invention, said gel particles having a size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm. The implant, in turn, is useful in a method of soft tissue augmentation in a mammal, including man, comprising subepidermal administration at a site in said mammal where soft tissue augmentation is desirable, of an implant comprising injectable gel particles of a viscoelastic medium, a major volume of said particles having a size, when subjected to a physiological salt solution, in the range of from 1 to 5 mm.
The term "soft tissue augmentation", as used herein, refers to any type of volume augmentation of soft tissues, including, but not limited to, facial contouring (e.g. more pronounced cheeks. or chin), correction of concave deformities (e.g. post-traumatic, HIV associated lipoatrophy) and correction of deep age-related facial folds. Thus, soft tissue augmentation may be used solely for cosmetic purposes or for medical purposes, such as following trauma or degenerative disease.
The term "soft tissue", as used herein, refers to tissues that connect, support, or surround other structures and organs of the body. Soft tissue includeb muscles, fibrous tissues and fat.
The method according to the invention may be performed in any mammal, including man. It is preferred that that the method is performed in a human subject.
The terms "subepidermal administration" or "subcuticular administration", as ii.sed herein, refer to administration beneath the epidermis of the skin, including administration into the dermis, subcutis or deeper, such as submuscularly or into the periosteum where applicable (in the vicinity of bone tissue).
Administration may be performed in any suitable way, such as via injection from standard cannulae. and needles of appropriate sizes.'The administration is performed where the soft tissue augmentation is desired, such as the chin, cheeks or elsewhere in the face or body.

The term "implant"., as used herein, refers' widely to any type of implanted or implantable foreign object or material. Implants also include objects or materials that are nearly identical to non-foreign objects or materials.
The implant according to the-invention is not Limited to any particular shape. The final shape of the implant in the body is decided by the skilled man from the purpose of the treatment.
By the term "viscoelastic medium", as used herein, is meant a medium that exhibits a combination of viscous and elastic properties. Specifically, the visco elastic medium according to the invention is injectable through.a gauge or larger needle, such as a 10-20 gauge needle, by application of a pressure of 15-50 N. In particular, 15 the medium, or an implant or a medicament comprising the medium, is suitable for subepidermal injection into a human in need thereof at a desired site.
Viscoelastic media according to the invention include gels, dispersions, solutions, suspensions, 20 slurries and mixtures thereof. It is preferred that the medium is present' as a dispersion of gel or gel-like particles. In a preferred embodiment, the implant according to the invention consists of 1-5 mm large particles of one or more viscoelastic media dispersed in a physiological salt buffer or a suitable physiological.
salt solvent. In another preferred embodiment, the implant further comprises other suitable additives, such as local anesthetics, anti-inflammatory drugs, antibiotics and other suitable supportive medications, e.g. bone growth factors or cells. Optionally, there may also be included a viscoelastic medium, which may be the same or different, which is not present as particles or as particles of a size smaller than 0.1 mm.
It goes without saying that the size of the gel particles according to the invention is dependent upon the ionic strength of the buffer, solution or ca-rrier that is included in and/or surrounding the gel particles.

Throughout this specification, given particle sizes assume physiological conditions, particularly isotonic conditions. It shall be noted that, while it is preferred that the gel particles contain and are dispersed in a physiological salt solution, it is contemplated that the gel particles according to the invention can temporarily be brought to different sizes by subjecting the gel particles to a solution of another b onicity. Particles that are within the scope of this invention exhibit a particle size within the given ranges under physiological conditions, e.g. when implanted subepidermally in the body or when subjected to a physiological, or isotonic, salt solution, i.e. a solution with the same tonicity as the relevant biological fluids, e.g. isoosmotic with serum.
Thus, the viscoelastic medium according to the invention is present at least as'geL particles or gel-like particles. A major volume, or more than 50% (v/v), of the particles have a size of at 1 east 1 mm, preferably in the range of 1-5 mm in the presence of a physiological salt solution. In preferred embodiments, more than 70%
(v/v), preferably more than 90% (v/v-) , of the particles are within the given size limits under physiological conditions.
As used herein, a physiological, or isotonic, solution is a solution having an osmolarity in the range of 200-400 mOsm/l, preferably 250-350 mOsm/l, more preferably approximately 300 mOsm/l. For practical purposes, this osmolarity is easily achieved. by preparation of a 0.9% (0.154 M) NaCl solution.' A suitable way of obtaining a desired particle size involves producing a gel made of a v3.scoelastic medium at a desired concentration and subjecting the gel to physical disruption, such as mincing. mashing or allowing the gel to pass through a filter with suitable pore size.
The resulting gel particles are dispersed in a physiological salt solution, resulting in a gel dispersion or slurry with particles of desired size.

Another aspect of the invention is the density, or 5 hardness, of the gel particles. The gel particle density can readily be regulated by adjustment e.g. of the concentration of the viscoelastic medium and the amount and type of cross-linking agent, if any. Thus, harder particles can be achieved by a higher concentration of 10 the viscoelastic medium in the gel, and thereby in the resulting gel particles. Harder particles are generally less viscoelastic and have a longer half-life in vivo than softer particles. For use in the present invention, it is critical that the particles retain enough viscoelastic properties so that they are still injectable.
In a preferred embodiment of the Lnvention, the implant is a two-component composition, consisting of softer gel particles mixed with harder gel particles. The gel particles may be made of the same or different viscoelastic media. The resulting mixture of gel particles combines desirable properties of softness/hardness for use in soft tissue augmentation and long durability in vivo.
Administration of the implant empLoying the method according to the invention prevents or diminishes migration and/or displacement of the implant, which comprises or consists of the 1-5 mm large particles under physiological conditions. A further advantage of the invention is that the large size of the particles in combination with the prevented or diminished migration facilitate easy removal of the implant comprising the particles, should it be desired for some reason.
In a preferred embodiment of the invention, the particles have a size in the range of from 1 to 2.5 mm, such as from 1.5 to 2 mm, in the presence of a physiological salt solution. These particles are suitable for administration to subcutaneous, submuscular or supraperiostal tissue. In particular, they are suitable for administration to tissues covered by skin that is exposed in public, such as facial tissue, since the particles and needles that are suitable for this particle size range are not likely to cause bruises or other discolorations. In a preferred embodiment, these particles are administered to deep subcutaneous or to submuscular/supraperiostal tissue, optionally in more than one layer. Deep subcutaneous or submuscular/supraperiostal administration further prevents or diminishes migration of the particles away from the desired site. According to this embodiment, a major volume, or more than 50% (v/v) , preferably more than 70% (v/v), more preferably more than 90% (v/v), of the particles are within the given size limits under physiological conditions.
In another embodiment of the invention, the particles have a size in the range o from 2.5 to 5 mm,, such as from 3 to 4 mm, in the presence of a physiological salt solution. Implants comprising such particles further prevents or diminishes migration of the particles away from the desired site_ According to this embodiment, a major volume, or more than 50% (v/v) , preferably more than 70% (v/v), more preferably more than 90% (v/v), of the particles are within the given size limits under physiological conditions.
Particle size may be determined in any suitable way, such as by laser diffraction, microscopy, filtration, etc, and is decided by the longest distance between two ends of the particle. The specific sb.ape of the gel particles is not critical. For. spherical particles, the diameter equals the size for this purpose. The size range may be regulated by mechanical disruption, such as mincing, mashing, filtration, etc, of a gel of a suitable concentration of the desired viscoela stic medium.

Viscoelastic media according to the invention include, without being limited thereto, polysaccharides and derivatives thereof. Suitable viscoelastic media include stabilized starch and derivatives thereof.
Suitable viscoelastic media can also be selected from stabilized glycosaminoglycans and derivatives thereof, such as stabilized hyaluronic acid, stabilized chondroitin sulfate, stabilized heparin, and derivatives thereof. Suitable viscoelastic media also include stabilized dextran and derivatives thereof, such as dextranomer. The viscoelastic medium may also be a combination of two or more suitable viscoelastic media.' By the term "stabilized", as used herein, is meant any form of chemical stabilization that, under physiological conditions, renders he stabilized compound more stable to biodegradation that the parent compound.
Without being limited thereto, stabilized compounds include cross-linked compounds and partially cross-linked compounds.
By the term "derivative" of a polysaccharide, as ' used herein, is meant any suitable derivative thereof, including cross-linked polysaccharides and substituted polysaccharides, such-as sulfated polysaccharides.
Viscoelastic media according to the invention are biocompatible, sterile and present as particles that are readily injectable through standard needles used in medicine, such as 20 gauge or larger needles, preferably 10-20 gauge needles. It is preferable that the viscoelastic medium is of non-animal origin.
Advantageously, the media according to the invention are stable, but not permanent, under physiological conditions. According to an embodiment of the invention, at least 70%, preferably at least 90%, of the viscoelastic medium remains for at ::Least two weeks in vivo, more preferably between two weeks and two years.
The viscoelastic medium according to the invention is preferably degraded after five years or more in vivo. The term "degraded" implies that less than 200, preferably less than 10%, of the medium remains in the body.
The viscoelastic medium according to the invention is more resistant to biodegradation in vivo than natural hyaluronic acid. The prolonged presence of the stable viscoelastic substance is advantageous for- the patient, since the time between treatments is increased.

A preferable viscoelastic medium according to the invention is cross-linked hyaluronic acid and derivatives thereof. One type of suitable cross-linked hyaluronic acid is obtainable by cross-linking of by .luronic acid, optionally non-animal, using the method of US patent 5,827,937.
In brief, said method involves forming an aqueous solution of a water soluble, cross-linkable polysaccharide; initiating a cross-linking of the polysaccharide in the presence of a polyfunctional cross-linking agent; sterically hindering the cross-linking reaction from terminating before gelation occurs, whereby an activated polysaccharide is obtained; and reintroducing sterically unhindered conditions for the activated polysaccharide so as to continue the cross-linking thereof up to a viscoelastic gel.
The cross-linking agent to be used ira connection with this particular method is any previously known cross-linking agent useful in connection with polysaccharides, consideration being taken to ensure that the biocompatibility prerequisites are fuLfilled.
Preferably, however, the cross-linking agent is selected from the group consisting of aldehydes, epoxides, polyaziridyl compounds, glycidyl ethers arid divinylsulfones. Of these, glycidyl ethers represent an especially preferred group, of which 1,4-butanediol diglycidyl ether can be referred to as a preferred example.

In this particular method, the initial cross-linking reaction in the presence of a polyfunctional cross-linking agent can be performed at varying pH values, primarily depending on whether ether or ester reactions should be promoted.
An example of a preferred viscoelastic medium is non-animal stabilized hyaluronic acid, commercially available from Q-Med AB, Uppsala, Sweden.

When the injectable medium is a hyaluronic acid medium, the hyaluronic acid concentration is 5 mg/ml or higher. It is preferred that the hyaluronic acid concentration is in the range o f 5-100 mg/ml, more preferred 10-50 mg/ml, such as approximately 20 mg/ml.
The cross-linked hyaluronic acid is present as particles or beads of any form. According to this embodiment, a major volume, or more than 50% (v/v), preferably more than 70% (v/v), more preferably more than 90% (v/v), of the particles are at least 1 mm in size, preferably in the range of 1-5 mm. As outlined above, a preferred embodiment involves particles in the range of 1-2.5 mm, preferably 1.5-2 mm. -Another preferred embodiment involves particles i:n the range of 2.5-5 mm, preferably 3-4 mm.
A suitable way of obtaining a desired particle size involves producing a gel made of cross-linked hyaluronic acid at a desired concentration and subjecting the gel to physical disruption, such as miricing, mashing or allowing the gel to pass through a filter with suitable particle size. The resulting gel particles are dispersed in a physiological salt solution, resulting in a gel.
dispersion or slurry with particles of desired size.

Another aspect of the invention is the density, or hardness, of the particles. Using the manufacturing method of the invention, the cross-linked hyaluronic acid particle density can readily be regulated by adjustment of the concentration of the viscoelastic medium and the amount and type of cross-linking agent. Thus, harder particles can be achieved by a higher concentration of the viscoelastic medium in the gel, and thereby in the 5 resulting gel particles. Harder particles are generally less viscoelastic and have a longer half-life in vivo than softer particles. Useful hyaluronic acid concentrations. yielding gel particles of varying hardness are e.g. 20, 25, 40, 50 and 100 mg/m1. For use in the 10 present invention, it is critical that the particles retain enough viscoelastic properties so that they are still injectable as discussed above.
In a preferred embodiment of the invention, softer gel particles, e.g. 15-22 mg/ml cross-linked hyaluronic 15 acid, are mixed with harder gel particles, e.g. 22-30 mg/ml cross-linked hyaluronic acid. The resulting mixture of gel particles combines desirable properties of softness/hardness for use in soft tissue augmentation and long durability in vivo.
According to the invention, the viscoelastic medi=G.m is administered, preferably injected, under the epidermis in any suitable way. By way of example, a dermal incision can be made with a scalpel or a sharp injection needle to facilitate transdermal insertion of a larger cannula for administration of the implant accordLng to the invention at the desired site. It is preferred that the administration is performed subcutaneously, submuscularly or supraperiostally.
The implant, consisting of particles of a viscoelastic medium and optionally other suitable ingredients, may be administered as a single aliquot or as layers of multiple aliquots. Optionally, the viscoelastic medium may be replaced, refilled or' replenished by a subsequent injection of the same or another viscoelastic medium. The injected volume is determined by the desired augmentation. In a typical tissue augmentation, a volume in the range of 1-500 ml is injected, depending on the purpose and the treated tissue.

According to another aspect of the invention, there is provided a novel use of particles of a viscoelastic medium according to the inverition, a major volume of said particles having an average size in the range of from 1 to 5 mm, for the manufacture of a medicament for therapeutic soft tissue augme]atation in a mammal, including man, wherein said medicament is suitable for subepidermal administration according to the invention at a site in said mammal where therapeutic soft tissue augmentation is desirable.
According to this aspect., it is preferred that the administration is performed subcutaneously, submuscularly or supraperiostally. The discussion hereinabove regarding suitable particle sizes applies also for this aspect of the invention.
As used herein, the term "therapeutic" involves any kind of preventive, alleviating or curative treatment.
Without being limited thereto, this aspect of the invention encompasses that the medicament is for"
reconstructive augmentation resulting from a medical condition and is part of a medical treatment of the condition. Thus, the therapeutic use is distinguishable from the non-medical, or cosme-tic, use in that they are directed to different patient groups. Specifically, the therapeutic use is solely dire-cted to patients in need of reconstructive augmentation resulting from a medical condition and constitutes a part of a medical treatment of this condition in these patients.

Without being limited thereto, the present invention will in the following be further illustrated by way of examples.

EXAMPLES

Example 1 Preparation of gel particles of non-animal stabilized hyaluronic acid As previously exemplified in e.g. US patent 5,827,937, 10 g of hyaluronic acid prepared by fermentation of Streptococcus was dissolved in 100 ml of 1% NaOH, pH>9. Cross-link:ing agent in the form of 1,4-butanediol diglycidyl ether was added to a concentration of 0.2%. The solution was incubated at 40 C for 4 h.
The incubated solution was diluted with an acidic water solution to reach neutral pH under mixing, yielding a final hyaluronic acid concentration of 20 mg/ml, and again incubated for 12 h at 70 C. The viscoelastic slurry that resulted from this second incubation was then cooled to room temperature and mashed to its final particle size, approximately 1.5-2 mm.

Example 2 Cheek and chin augmentation Materials ' A clear, colorless, viscoelastic gel consisting of non-animal stabilized hyaluronic acid (20 mg/ml) dispersed in physiological saline solution. The gel is obtainable e.g.
by the method of example 1. The sterilized study material (2 ml) was supplied in a 3 ml glass syringe and was injected subcutaneously and/or supraperiostally using a sterilized 16G x 7 or 9 crn Coleman infiltration cannula with a blunt tip (Byron Medical Inc., Tucson, Arizona, USA).

Patient selection and study design Adult outpatients (>18 years of age) of. either gender seeking cheek and/or chin augmentation therapy for aesthetic purposes. For study inclusion, patients were required to agree to abstain from'other cosmetic procedures (e.g., further augmentation therapy, botulinum toxin injections, laser or chemical skin resurfacing or facelift procedures) for the duration of the study.
Patients who had undergone facial tissue augmentation therapy or laser/chemical peeling procedures within the previous 6 months or aesthetic facial surgery within the previous 12 months were excluded from the study, In addition, patients presenting with active skin disease or inflammation affecting the intended treatment area, those with known allergy/hypersensitiv-ity to local anaesthetics or previous adverse reactions to NASHA, and those currently taking anticoagulant c >r antiplatelet drugs were excluded from participation. The use of anticoagulants,.
aspirin and non-steroidal anti-inflammatory drugs was prohibited until the injection site had completely healed.

Injection technique The treatment area was cleaned with an antiseptic solution and, if local anaesthesia was required, lidocaine (0.5 or 1.0%) /adrenaline solution was injected at the planned incision site. Additional anaesthesia was provided, if required, by regional nerve block or subcutaneous injection of lidoca ine/adrenaline at the proposed implantation site. A dermal incision 1-2 mm in length was made with a scalpel (11 blade) or sharp injection needle to facilitate t ransdermal insertion of a 16G blunt-tipped cannula for administration of the gel into the subcutaneous, submuscular or supraperiostal adipose tissue. The gel was injected in small aliquots throughout the area requiring augmentation, rather than as a single bolus, by manipulating the cannula into a different tract after each inject ion, using a tunnelling technique. A maximum of 10 ml (5.syringes) of gel was administered at each treatment session to.a maximum of 3 separate anatomical sites (chin and both cheeks). On completion of the injection, the treatment area was massaged to conform to the contour of the surrounding tissue and, if necessary, ice was applied briefly to reduce any swelling.
Satisfactory cheek and/or chin augmentation for at least 3 months was obtained by the method. In particular, deep subcutaneous injection and supraperiostal injection further prevented migration of the implant.

Example 3 Preparation of gel particles of non-animal stabilized hyaluronic acid with longer duration.
Ten grams of hyaluronic acid prepared by fermentation of Streptococcus was dissolved in 100 ml of ,1% NaOH,. pH>9. Cross-linking agent in the form of 1,4-butanediol diglycidyl ether was added to a concentration of 0.2%. The solution was incubated at 40 C for 4 h.
The alkaline gel was divided in two portions, which were individually diluted with an acidic water solution to reach neutral pH under mixing, yielding final hyaluronic acid concentrations of 20 mg/ml and 25 mg/ml, respectively. The gels were incubated for 12 h at 70 C
and cooled to room temperature. The two gel portions were combined and mashed t c) the final particle size, ' approximately 3-4 mm.

Example 4 Breast tissue augmentation.
Women with small breasts were injected with a gel obtainable e.g. by the method of example 3. Each breast received 100 ml gel implanted under the glandular region, just on the pectoralis muscle, using a blunt 12 G needle in small aliquots. Care was taken not to disturb the natural tissue. Twelve months following implantation, the breasts were still in good shape with thin nodular implants. The implant did not blur the analysis of .mammography.
One woman had changed her mind about having gels in her breasts and requested for removal of the implant. A
blunt cannulae (12 G) was used to suck back the gel.
Almost all. of the implant was aspirated as a clear transparent'gel fluid..Analy-sis showed that the gel maintained its volume but was slightly lower in concentration as compared tc the initial concentration (75% of initial), indicating an implant duration of about 5 2-3 years.

Claims

CLAIMS:

1. Particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, which particles are injectable gel particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm.

2. Particles according to claim 1, wherein said size is in the range of from 1.5 to 2.5 mm.

3. Particles according to claim 1, wherein said size is in the range of from 2.5 to 5 mm.

4. Particles according to claim 3, wherein said viscoelastic medium is selected from the group consisting of cross-linked hyaluronic acid and derivatives thereof.

5. Particles according to claim 4, wherein the concentration of said viscoelastic medium in said gel particles, when subjected to a physiological salt solution, is in the range of from 5 to 100 mg/ml.

6. Particles according to any one of claims 1 to 5, which are injectable through a 20 gauge or larger needle by application of a pressure of 15-50 N.

7. A method of producing injectable gel particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, comprising the steps of:

(i) manufacturing a gel with a desired concentration of said viscoelastic medium; and (ii) mechanically disrupting said gel into gel particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm.

8. A soft tissue augmentation implant comprising particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, wherein more than 50% (v/v) of said particles are injectable gel particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm.

9. A soft tissue augmentation implant according to claim 8, wherein said size is in the range of from 1.5 to 2.5 mm.

10. A soft tissue augmentation implant according to claim 8, wherein said size is in the range of from 2.5 to 5 mm.

11. Use of an implant comprising injectable gel particles of a viscoelastic medium, wherein said viscoelastic medium is selected from stabilized hyaluronic acid and derivatives thereof, more than 50% (v/v) of said particles having a size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm, for soft tissue augmentation in a mammal, wherein the implant is for subepidermal administration at a site in said mammal where soft tissue augmentation is desirable.

12. Use according to claim 11, wherein the implant is for subcutaneous administration.

13. Use according to claim 11, wherein the implant is for submuscular administration.

14. Use according to claim 11, wherein the implant is for supraperiostal administration.

15. Use according to any one of claims 11-14, wherein said size is in the range of from 1.5 to 2.5 mm.

16. Use according to any one of claims 11-14, wherein said size is in the range of from 2.5 to 5 mm.

17. Use according to claim 15, wherein said site of soft tissue augmentation is selected from facial tissue and other tissues covered by exposed skin.

18. Use according to any one of claims 11-17, wherein the implant is for soft tissue augmentation in a single administration.

19. Use according to any one of claims 11-17, wherein the implant is for soft tissue augmentation in a multiple-layer administration.

20. Use according to any one of claims 11-19, wherein said mammal is a human.

21. Injectable gel particles according to any one of claims 1-6 for use as a medicament.

22. An injectable soft tissue augmentation implant comprising injectable gel particles according to any one of claims 1-6 for use as a medicament.

23. Use of injectable gel particles of a viscoelastic medium according to any one of claims 1-6, more than 50% (v/v) of said particles having an average size, when subjected to a physiological salt solution, in the range of from 1.5 to 5 mm, for the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, wherein said medicament is for subepidermal administration at a site in said mammal where therapeutic soft tissue augmentation is desirable.