HK1150984A - Particles for soft tissue augmentation - Google Patents

Description

Particles for soft tissue augmentation

The application is a divisional application with application date of 2005, 4 and 7, application number of 200580014103.2, entitled "granule for soft tissue augmentation".

Technical Field

The present invention relates to the field of cosmetic and plastic surgery, including cosmetic and reconstructive surgery. More particularly, the present invention relates to a method of soft tissue augmentation in mammals, including humans. Furthermore, the present invention relates to the use of particles of a viscoelastic medium for the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, including a human. The invention also relates to particles of a viscoelastic medium, products thereof, and their use in implants.

Background

Implant materials for soft tissue augmentation ideally should be able to provide adequate and durable cosmetic and/or therapeutic correction without migration and displacement; has a natural appearance and is not tactile; easy to apply and, if desired, easy to remove; non-immunogenic; and no chronic inflammatory response (Krauss MC, Semin Cutan Med Surg 1999; 18: 119-. As a soft tissue augmentation material, hyaluronic acid, a natural polysaccharide, has a low immunogenic potential and can be homogeneously chemically cross-linked into all species and tissues (Larsen NE et al, J biomedMater Res 1993; 27: 1129 1134). The stabilization (or cross-linking) of the hyaluronic acid molecule can improve its resistance to enzymatic degradation without compromising its biocompatibility, whereas the use of hyaluronic acid of non-animal origin reduces the possibility of antigen contamination and subsequent development of hypersensitivity reactions (Friedman et al, Dermatol Surg 2002; 28: 491-4).

In US5,827,937, non-animal stable hyaluronic acid (NASHA) can be prepared by bacterial fermentation of a high purity hyaluronic acid preparation. Various NAHA preparations of different particle sizes have been developed: (Perlane，Fine Lines andtouch, all from Q-Med AB, Uppsala, Sweden) as a skin filler material for facial soft tissue augmentation. Clinical studies have shown that the known NASAH gels improve facial wrinkles and folds in lip augmentation (Bousset M-T and Agerup B, Oper Techniques Occuplate Orbit Reconstrut Surg 1999; 2: 172-(Ocenius M. Aestplat Surg 1998; 22: 97-101; Duranti F et al, Dermatol Surg 1998; 24: 1317-25; NarinsRS et al, Dermatol Surg 2003; 29: 588-95; Carruther J and Carruther A, Dermatol Surg 2003; 29: 802-9) which provide a more permanent cosmetic improvement than bovine collagen or hylan B. They were proven safe by extensive clinical experience in their 150 ten thousand facial cosmetic procedures for the dermis.

According to recommendations RESTYLANE Touch (-500,000 particles/ml, average particle size 0.2mm) should be injected into the upper part of the dermis; RESTYLANE (. about.100,000 particles/ml, with an average particle size of about 0.4mm) should be injected into the more medial portion of the dermis; and RESTYLANE Perlane (-10,000 particles/ml, average particle size about 0.8mm) should be injected into the deep layer of the dermis and/or the superficial layer of the subcutaneous tissue.

Some known soft tissue augmentation treatments involving the implantation of viscoelastic materials occasionally suffer from the following disadvantages: the implant or portions thereof may migrate from the site in need of treatment. Another problem with some known soft tissue augmentation treatments involving the implantation of viscoelastic materials is that the implant can become dislodged from the site requiring treatment. Migration and displacement are undesirable for the patient as they can compromise the cosmetic and/or therapeutic efficacy of the treatment and can also be an impediment if removal of the implant is required.

Brief description of the invention

It is an object of the present invention to provide an implant material suitable for soft tissue augmentation which overcomes the disadvantages of known implant materials. It is also an object of the present invention to provide a method for preparing the implant material.

Another object is to provide an implant suitable for soft tissue augmentation comprising the above mentioned implant material which overcomes the disadvantages of the known implants. It is a further object of the present invention to provide an implant suitable for soft tissue augmentation comprising the above-described implant material that can be easily removed if desired.

It is another object of the present invention to provide a method for soft tissue augmentation in mammals, including humans, which overcomes the disadvantages of the known methods. It is an object of the present invention to provide a method for soft tissue augmentation in mammals, including humans, comprising the sub-epidermal administration of an implant, which may avoid or reduce unwanted migration of the implant from the site in need of implantation. It is an object of the present invention to provide a method for soft tissue augmentation in mammals, including humans, comprising administering an implant under the epidermis, which may avoid or reduce migration of the implant from the site in need of implantation.

It is also an object of the present invention to provide the use of a viscoelastic medium for the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, including a human.

To achieve these objects and others which will become apparent from the following disclosure, the present invention provides particles of a viscoelastic medium which, when present in a physiological salt solution, is an injectable gel having a particle size of 1 to 5 mm.

The present invention is based on the following findings: subcutaneous administration of an implant comprising gel particles comprised of a viscoelastic medium, which is much larger than the media comprised of viscoelastic medium previously used in implants, may prevent migration and/or displacement of the implant or portions thereof from the site where soft tissue augmentation is desired. Furthermore, the combination of limited displacement of the implant and the relatively large particle size facilitates easy removal of the implant when desired.

In certain preferred particles according to the invention, the particle size is 1 to 2.5 mm. In other preferred granules according to the invention, the particle size is 2.5 to 5 mm.

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

In a preferred particle according to the invention, the viscoelastic medium is selected from cross-linked hyaluronic acid and derivatives thereof. In particularly preferred particles according to the invention, the concentration of the viscoelastic medium in the gel particles is from 5 to 100mg/ml when present in a physiological salt solution.

Preferred particles according to the invention are injectable, which can be injected with a needle of size 20 or greater, using a pressure of 15-50N.

According to another aspect of the present invention, there is provided a method of preparing injectable gel particles of a viscoelastic medium, comprising the steps of: (i) preparing a gel with a desired concentration of the viscoelastic medium; and (ii) mechanically breaking the gel into gel particles having a particle size of 1 to 5mm when present in a physiological salt solution.

According to another aspect of the present invention there is provided a soft tissue augmentation implant comprising particles of a viscoelastic medium, wherein the majority volume of said particles are injectable gel particles having a particle size of 1 to 5mm when present in a physiological salt solution. In a preferred embodiment of the implant, said particle size is 1 to 2.5 mm. In other preferred embodiments of the implant, the particle size is 2.5 to 5 mm.

According to one aspect of the present invention there is provided a method of soft tissue augmentation in a mammal, including a human, comprising administering subcutaneously at a site in said mammal where soft tissue augmentation is desired an implant comprising injectable gel particles of a viscoelastic medium, the majority volume of said particles having a particle size of from 1 to 5mm when present in a physiological salt solution. In a preferred embodiment of the method according to the invention, said administration is selected from subcutaneous administration, submuscular administration and supraperiosteal administration.

In certain processes according to the present invention, the particle size is 1 to 2.5 mm. In a preferred embodiment of the method, the soft tissue augmentation site is selected from facial tissue and other tissue covered by exposed skin. In other processes according to the invention, the particle size is from 2.5 to 5 mm.

In a preferred method according to the invention, the application is selected from the group consisting of a single application and a multi-layer application.

According to another aspect of the invention, there is provided an injectable gel particle according to the invention for use as a medicament. Injectable soft tissue augmentation implants comprising injectable gel particles according to the invention are also provided for use as medicaments.

According to another aspect of the present invention there is provided the use of injectable gel particles of a viscoelastic medium according to the present invention in the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, including a human, wherein the majority volume of said particles has an average particle size of from 1 to 5mm when present in a physiological salt solution, wherein said medicament is suitable for administration subcutaneously according to the present invention at a site in said animal requiring therapeutic soft tissue augmentation.

Detailed Description

According to one aspect of the present invention there is provided particles of a viscoelastic medium which are injectable gel particles having a particle size of from 1 to 5mm when present in a physiological salt solution. The particles are useful in soft tissue augmentation implants comprising particles of a viscoelastic medium, wherein according to the invention a majority volume of said particles are injectable gel particles, the particle size of said gel particles being from 1 to 5mm when present in a physiological salt solution. In turn, the implant is useful in a method of soft tissue augmentation in a mammal, including a human, comprising administering subcutaneously at a site in said mammal in need of soft tissue augmentation an implant comprising injectable gel particles of a viscoelastic medium, the majority volume of said particles having a particle size of from 1 to 5mm when present in a physiological salt solution.

The term "soft tissue augmentation" as used herein relates to any form of soft tissue volume increase, including but not limited to facial contours (e.g., more specifically, the cheeks, or the chin), correction of concave deformities (e.g., post-trauma, HIV-associated lipoatrophy), and correction of age-related deeper facial folds. Thus, soft tissue augmentation may be used alone for cosmetic or medical purposes, such as trauma or degenerative diseases as follows.

The term "soft tissue" as used herein refers to tissue that connects, supports or surrounds other structures or organs of the body. Soft tissue includes muscle, fibrous tissue and fat.

The method according to the invention may be used in any mammal, including humans. Preferably the method is for use with a human patient.

The term "sub-epidermal administration" or "sub-stratum corneum administration" as used herein relates to administration under the epidermis of the skin, including administration to the dermis, the subcutaneous tissue, or deeper, e.g., under the muscle, or into the periosteum (in the vicinity of the bone tissue) as appropriate.

Administration may be by any suitable method, for example injection through a standard cannula and a needle of appropriate size. Administration is performed if soft tissue augmentation is required, for example, in the chin, cheeks, or other sites of the face or body.

The term "implant" herein broadly refers to any form of implanted or implantable external object or material. Implants also include objects or materials that are nearly identical to non-external 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 determined by the skilled person according to the purpose of the treatment.

The term "viscoelastic medium" herein refers to a medium that exhibits a combination of viscosity and elasticity. In particular, the viscoelastic medium according to the invention is injectable, which can be injected through a 20 gauge or larger needle, for example a 10-20 gauge injection needle, by applying a pressure of 15-50N. In particular, the medium or the implant or drug comprising the medium is suitable for subcutaneous injection to a person in need thereof at a desired site.

Viscoelastic media according to the invention include gels, dispersions, solutions, suspensions, slurries and mixtures thereof. Preferably the medium is present as a dispersion of a gel or gel-like particles. In a preferred embodiment, the implant according to the invention comprises 1-5mm larger 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 agents, antibiotics, or other suitable supportive drugs, such as bone growth factors or cells. Optionally, the same or different viscoelastic medium is also included, which is not present in the form of particles, or is present in the form of particles having a particle size of less than 0.01 mm.

It goes without saying that the size of the gel particles according to the invention depends on the ionic strength of the buffer, solution or carrier comprising and/or surrounding the gel particles. Throughout this specification, the size of a given particle is assumed to be under physiological conditions, particularly isotonic conditions. It should be noted that while it is preferred that the gel particles be contained and dispersed in a physiological salt solution, it is contemplated that the gel particles according to the present invention may be temporarily formed into different particle sizes by using the gel particles in solutions of other tonicity. Particles within the scope of the present invention show a particle size within the given range under physiological conditions, e.g. when implanted subcutaneously in vivo or used in physiological or isotonic saline solvents, i.e. solutions having the same tonicity as the relevant physiological fluid, e.g. isotonic with serum.

The viscoelastic medium according to the invention is thus present at least as gel particles or gel-like particles. When present in a physiological salt solution, the majority of the volume or particles exceeding 50% (v/v) have a particle size of at least 1mm, preferably 1-5 mm. In a preferred embodiment, more than 70% (v/v), more preferably more than 90% (v/v) of the particles are within the given particle size range under physiological conditions.

Here, the physiological or isotonic solution is a solution having an osmolality of 200-400mOsm/l, preferably 250-350mOsm/l, more preferably about 300 mOsm/l. For practical purposes, this osmolality can be easily achieved by preparing a 0.9% (0.154M) NaCl solution.

Suitable methods for achieving the desired particle size include preparing a gel of viscoelastic medium at the desired concentration and physically breaking the gel, for example by chopping, mashing or passing the gel through a filter of suitable pore size. The resulting gel particles are dispersed in a physiological salt solution to obtain a gel dispersion or slurry containing particles of a desired particle size.

Another aspect of the invention is the density or hardness of the gel particles. The density of the gel particles can be easily adjusted by adjusting, for example, the concentration of the viscoelastic medium and, if any, the amount and type of crosslinking agent. Thus, the use of higher concentrations of viscoelastic medium in the gel and thus the resulting gel particles may result in stiffer particles. Harder particles generally have less viscoelastic properties and a longer half-life in vivo than softer particles. For use in the present invention, it is critical that the particles retain sufficient viscoelastic properties so that they can still be injected.

In a preferred embodiment of the invention, the implant is a two-component composition comprising a mixture of softer gel particles and harder gel particles. The gel particles may be composed of the same or different viscoelastic media. The resulting mixture of gel particles combines desirable soft/hard properties, can be used for soft tissue augmentation and has longer durability in vivo.

Implants administered in accordance with the methods of the present invention prevent or reduce migration and/or replacement of the implant, wherein the implant comprises or consists of large particles that are 1-5mm under physiological conditions. Another advantage of the present invention is that larger particles plus their hindered or reduced migration facilitate the ease with which an implant containing the particles can be removed when removal is required for some reason.

In a preferred embodiment of the invention, the particles have a particle size of 1 to 2.5mm, for example 1.5 to 2mm, when a physiological salt solution is present. These particles are suitable for administration to subcutaneous, submuscular or supraperiosteal tissues. In particular, they are suitable for application to tissue covered by public exposed skin, such as facial tissue, as having particles and needles adapted to this range of particle sizes does not result in bruising or other discolouration. In a preferred embodiment, these particles are administered, optionally in more than one layer, either subcutaneously deeper or to the sub-muscularis/supraperiosteal tissue. Administration to deeper subcutaneous or submuscular/supraperiosteal tissues further prevents or reduces migration of particles from the desired site. According to this embodiment, under physiological conditions, a majority volume, or more than 50% (v/v), preferably more than 70% (v/v), more preferably more than 90% (v/v), of the particles is within the given particle size range.

In another embodiment of the invention, the particles have a particle size of 2.5 to 5mm, for example 3 to 4mm, when a physiological salt solution is present. Implants containing the particles can also prevent or reduce migration of the particles from a desired site. According to this embodiment, under physiological conditions, a majority volume, or more than 50% (v/v), preferably more than 70% (v/v), more preferably more than 90% (v/v), of the particles is within the given particle size range.

The particle size may be determined by any suitable method, for example by laser diffraction, microscopy, filtration, etc., by the longest distance between the 2 ends of the particle. The particular shape of the gel particles is not critical. For spherical particles, the diameter is equal to the diameter for the purpose. The particle size range of the gel of the desired viscoelastic medium at the appropriate concentration can be adjusted by mechanical disruption, e.g., chopping, trituration, filtration, and the like.

Viscoelastic media according to the present invention include, but are not limited to, polysaccharides and derivatives thereof. Suitable viscoelastic media include stabilized starches and their derivatives. Suitable viscoelastic media may also be selected from the group consisting of stabilized glycosaminoglycans and derivatives thereof, such as stabilized hyaluronic acid, stabilized chondroitin sulfate, stabilized heparin and derivatives thereof. Suitable viscoelastic media also include stabilized dextrans and derivatives thereof, such as dextran anhydride. The viscoelastic medium may also be a combination of two or more suitable viscoelastic media.

The term "stable" as used herein refers to any chemical stabilization that renders a stable compound more stable under physiological conditions without biodegradation of the parent compound. Without being limited in any way, stable compounds include cross-linking compounds and partially cross-linking compounds.

The term "derivative" of a polysaccharide herein refers to any suitable derivative thereof, including cross-linked polysaccharides and substituted polysaccharides, such as sulfated polysaccharides.

The viscoelastic medium according to the invention is biocompatible, sterile and present in the form of particles which can be easily injected through standard needles used in medical treatment, such as 20 gauge needles or larger needles, preferably 10-20 gauge needles. Preferably the viscoelastic medium is of non-animal origin. Advantageously, the medium according to the invention is stable, but not invariable, under physiological conditions. According to one embodiment of the invention, at least 70%, preferably at least 90% of the viscoelastic medium may remain in vivo for at least 2 weeks, more preferably from 2 weeks to 2 years. The viscoelastic medium according to the invention preferably degrades in vivo after 5 years or more. The term "degrade" means that less than 20%, 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 native hyaluronic acid. The prolonged presence of the stable viscoelastic is beneficial to the patient due to the increased time between treatments.

According to the invention, the preferred viscoelastic medium is cross-linked hyaluronic acid and derivatives thereof. One type of suitable cross-linked hyaluronic acid is obtained by cross-linking an optional non-animal hyaluronic acid using the method of US5,827,937.

Briefly, the method comprises forming an aqueous solution of a water-soluble crosslinkable polysaccharide; (ii) initiating cross-linking of the polysaccharide in the presence of the multifunctional cross-linking agent; steric hindrance preventing the crosslinking reaction from terminating before gelation occurs, thereby obtaining an activated polysaccharide; the activated polysaccharide is reintroduced into steric non-hindering conditions to continue crosslinking until a viscoelastic gel is obtained.

The cross-linking agent used in this particular method is any cross-linking agent previously known to be useful in combination with polysaccharides, care being taken to ensure that the prerequisites for biocompatibility are met. However, it is preferred that the crosslinking agent is selected from the group consisting of aldehydes, epoxides, polyethylenimine compounds, glycidyl ethers, and divinyl sulfone. Among them, glycidyl ethers are a particularly preferred group of substances, and a preferred example thereof is 1, 4-butanediol diglycidyl ether.

In this particular method, the initial crosslinking reaction in the presence of the multifunctional crosslinking agent can be carried out at different pH values, depending mainly on whether the ether or ester reaction should be promoted.

Examples of preferred viscoelastic media are non-animal stable hyaluronic acids commercially available from Q-Med AB, Uppsala, Sweden.

When the injectable medium is a hyaluronic acid medium, the hyaluronic acid concentration is 5mg/ml or more. Preferably the concentration of hyaluronic acid is between 5 and 100mg/ml, more preferably between 10 and 50mg/ml, for example about 20 mg/ml.

The cross-linked hyaluronic acid is present as particles or beads in any form. According to this embodiment, the majority by volume, or more than 50% (v/v), preferably more than 70% (v/v), more preferably more than 90% (v/v), of the particles have a particle size of at least 1mm, preferably 1-5 mm. As mentioned above, a preferred embodiment comprises particles of 1-2.5mm, preferably 1.5-2 mm. Another preferred embodiment comprises particles of 2.5 to 5mm, preferably 3 to 4 mm.

Suitable methods for achieving the desired particle size include preparing a gel of cross-linked hyaluronic acid at the desired concentration, physically breaking the gel, for example by chopping, mashing or passing the gel through a filter of suitable pore size. The resulting gel particles are dispersed in a physiological salt solution to obtain a gel dispersion or slurry containing particles of a desired particle size.

Another aspect of the invention is the density or hardness of the particles. With the production method of the present invention, the density of the crosslinked hyaluronic acid particles can be easily adjusted by adjusting the concentration of the viscoelastic medium and adjusting the amount and type of the crosslinking agent. Thus, the use of higher concentrations of viscoelastic medium in the gel and thus the resulting gel particles may result in stiffer particles. Harder particles generally have less viscoelastic properties and a longer half-life in vivo than softer particles. Useful hyaluronic acid concentrations that produce gel particles of varying hardness are, for example, 20, 25, 40, 50 and 100 mg/ml. For use in the present invention, it is critical that the particles retain sufficient viscoelastic properties so that they are still injectable as described above.

In a preferred embodiment of the invention, softer gel particles, e.g. 15-22mg/ml cross-linked hyaluronic acid, are mixed with harder gel particles, e.g. 22-30mg/ml cross-linked hyaluronic acid. The resulting mixture of gel particles combines desirable soft/hard properties, can be used for soft tissue augmentation and has longer durability in vivo.

According to the present invention, the viscoelastic medium is administered subcutaneously in any suitable way, preferably by injection. By way of example, an epidermal incision is made with a scalpel or sharp injection needle to facilitate percutaneous insertion of a larger cannula for administration of an implant according to the present invention at a desired site. Preferably, administration is subcutaneous, submuscular or supraperiosteal.

The implant, which is composed of particles of a viscoelastic medium and optionally other suitable components, may be applied as a single part or as a multi-part layer. Optionally, the viscoelastic medium may be replaced, refilled or refilled by a subsequent injection of the same or another viscoelastic medium. The injection volume depends on the addition required. In a representative tissue augmentation, the injection volume is 1-500ml, depending on the purpose and tissue being treated.

According to another aspect of the present invention there is provided a novel use of particles of a viscoelastic medium in the manufacture of a medicament for therapeutic soft tissue augmentation in a mammal, including human, the majority by volume of said particles having a particle size of from 1 to 5mm, wherein said medicament is suitable for administration subcutaneously in accordance with the present invention at a site in said animal in need of therapeutic soft tissue augmentation.

According to this aspect, administration is preferably subcutaneous, submuscular or supraperiosteal 1 y. The above discussion of the appropriate particle size to apply also applies to this aspect of the invention.

The term "therapeutic" herein includes any kind of prophylactic, palliative or radical treatment. Without being limited in any way, this aspect of the invention includes the use of the medicament for reconstructive augmentation caused by a medical condition and as part of the medical treatment of that condition. Thus, the therapeutic uses differ from their non-medical or cosmetic uses directly in different patient groups. In particular, the therapeutic use is solely directed to patients in need of reconstructive augmentation caused by a medical condition, constituting part of a medical treatment in that condition of the patients.

Without any limitation, the present invention will be further illustrated by the following examples.

Examples

Example 1 preparation of non-animal Stable gel particles of hyaluronic acid

10g of hyaluronic acid prepared by fermentation of streptococci was dissolved in 100ml of 1% NaOH, pH > 9, as previously exemplified in U.S. Pat. No. 5,827,937. The crosslinker 1, 4-butanediol diglycidyl ether was added to a concentration of 0.2%. The solution was incubated at 40 ℃ for 4 hours.

The above cultured solution was diluted with an acidic aqueous solution so as to reach a neutral pH under mixing to give a final concentration of hyaluronic acid of 20mg/ml, and cultured at 70 ℃ for another 12 hours. The viscoelastic slurry from the second incubation is then cooled to room temperature and triturated to yield particles of about 1.5-2 mm.

EXAMPLE 2 cheek and chin filling

Material

A clear, colorless viscoelastic gel composed of non-animal stable hyaluronic acid (20mg/ml) was dispersed in a physiological saline solution. The gel is obtained, for example, by the method of example 1. A 3ml glass syringe was filled with sterile study material (2ml) and injected subcutaneously and/or supraperiosteally for 1y using a sterile 16G x 7 or 9 crn Coleman osmotic cannula with a blunt tip (byron medical inc., Tucson, Arizona, USA).

Patient selection and study design

Adult outpatients of any gender seeking additional treatment of the cheeks and/or chin for cosmetic purposes (> 18 years) were selected. To enroll in the study, patients were asked to avoid other cosmetic procedures (e.g., other add-on treatments, botulinum toxin injections, laser or chemical skin resurfacing or deflatface procedures) during the study. Patients who had undergone facial tissue augmentation or laser/chemical peeling procedures over the past 6 months or facial cosmetic surgery over the past 12 months were excluded from this study, as well as patients with active skin disease or inflammation affecting the area for which treatment was planned, patients with known allergic or allergic reactions to local anesthesia or previously adverse reactions to NASHA, and patients who were taking anticoagulants or antiplatelet drugs. Anticoagulant, aspirin and non-steroidal anti-inflammatory drugs are prohibited until the injection site is completely healed.

Injection technique

The area of treatment is cleansed with a disinfecting solution and, if local anesthesia is required, lidocaine (0.5 or 1.0%)/epinephrine solution is injected at the site of the planned incision. Additional anesthesia can also be provided, if desired, by regional nerve block at the site of intended implantation or by subcutaneous injection of lidocaine/epinephrine. A skin incision 1-2mm long was made with a scalpel (11-blade) or sharp injection needle to facilitate percutaneous insertion of a 16G blunt-ended cannula for gel application to subcutaneous, sub-muscular or supraperiosteal adipose tissue. With the tunnel technique, the gel is injected in small aliquots into the entire area to be filled, by inserting the cannula into different tubes after each injection, instead of being rapidly perfused. The maximum amount of gel administered at up to 3 individual anatomical sites (chin and two cheeks) per treatment time was 10ml (5 syringes). Once the injection is completed, the treatment area is massaged to conform to the surrounding tissue contours, and if necessary, ice may be temporarily applied to reduce any distension.

By this method, a satisfactory cheek and/or chin addition can be achieved for at least 3 months. In particular, deeper subcutaneous and supraperiosteal injections also prevent migration of the implant.

Example 3 preparation of non-animal Stable gel particles of hyaluronic acid with extended duration

10g of hyaluronic acid prepared by fermentation of streptococci was dissolved in 100ml of 1% NaOH, pH > 9. The crosslinker 1, 4-butanediol diglycidyl ether was added to a concentration of 0.2%. The solution was incubated at 40 ℃ for 4 hours.

The alkaline gel was divided into two portions, diluted with acidic aqueous solutions, respectively, such that a neutral pH was reached upon mixing, resulting in final concentrations of hyaluronic acid of 20mg/ml and 25mg/ml, respectively. The gel was incubated at 70 ℃ for 12 hours and cooled to room temperature. The two gel fractions were combined and comminuted to give granules of about 3-4 mm.

Example 4 augmentation of mammary tissue

Women with smaller breasts were injected with the gel obtained by the method of example 3, and 100ml of the gel was implanted in smaller aliquots into each breast, below the gland, above the pectoral muscle, using blunt 12G needles. Careful injection was performed so as not to damage the native tissue. The mammary gland containing the thinner nodular implant still maintained a good shape 12 months after implantation. The implant does not obscure the mammography analysis.

A woman who has implanted a gel in the mammary gland has changed mind, requiring the implant to be removed. The gel was aspirated back using a blunt cannula (12G). Almost all implants were aspirated in the form of a clear, transparent gel liquid. Analysis showed that the gel retained its volume about 2-3 years after implantation, but its concentration decreased slightly (75% of the initial) compared to the initial concentration.

Claims (24)

1. Particles of a viscoelastic medium which, when present in a physiological salt solution, are injectable gel particles having a particle size of from 1 to 5mm, wherein the viscoelastic medium is selected from polysaccharides.

2. The granule according to claim 1, wherein the particle size is 1 to 2.5 mm.

3. The granule according to claim 1, wherein the particle size is 2.5 to 5 mm.

4. A particle according to any of claims 1-3, wherein the viscoelastic medium is selected from cross-linked glycosaminoglycans.

5. A particle according to any of claims 1-3, wherein the viscoelastic medium is selected from the group consisting of cross-linked hyaluronic acid, cross-linked chondroitin sulfate, cross-linked heparin.

6. The particle according to any one of claims 1-3, wherein the viscoelastic medium is selected from cross-linked hyaluronic acid.

7. The particle according to claim 5, wherein the concentration of the viscoelastic medium in the gel particle is 5 to 100mg/ml when present in a physiological salt solution.

8. Particles according to any of claims 1 to 3 which can be injected through a needle of 20 gauge or larger by applying a pressure of 15 to 50N.

9. A method of preparing injectable gel particles of a viscoelastic medium selected from polysaccharides, comprising the steps of: (i) preparing a gel with a desired concentration of the viscoelastic medium; and (ii) mechanically breaking the gel into gel particles having a particle size of 1 to 5mm when present in a physiological salt solution.

10. A soft tissue augmentation implant comprising particles of a viscoelastic medium selected from polysaccharides, wherein the majority volume of the particles, when present in a physiological salt solution, are injectable gel particles having a particle size of 1 to 5 mm.

11. The soft tissue augmentation implant of claim 10, wherein the particle size is 1 to 2.5 mm.

12. The soft tissue augmentation implant of claim 10, wherein the particle size is 2.5 to 5 mm.

13. Use of injectable gel particles according to any one of claims 1 to 8 as a medicament.

14. An injectable soft tissue augmentation implant comprising injectable gel particles according to any one of claims 1 to 8.

15. Use of injectable gel particles according to any one of claims 1-8 for the preparation of a medicament for soft tissue augmentation in a mammal, including man, wherein the majority volume of said particles has a particle size of 1 to 5mm when present in a physiological salt solution, said medicament being suitable for administration beneath the epidermis of a site of said mammal in need of soft tissue augmentation.

16. Use according to claim 15, wherein the administration is subcutaneous administration.

17. Use according to claim 15, wherein the administration is a sub-muscular administration.

18. Use according to claim 15, wherein the administration is supraperiosteal.

19. Use according to any one of claims 15 to 18, wherein the particle size is from 1 to 2.5 mm.

20. Use according to any one of claims 15 to 18, wherein the particle size is from 2.5 to 5 mm.

21. Use according to claim 19, wherein the site of soft tissue augmentation is selected from facial tissue and other tissue covered by exposed skin.

22. Use according to any one of claims 15 to 18, wherein the administration is separate administration.

23. Use according to any one of claims 15-18, wherein the administration is a multi-layer administration.

24. Use of injectable gel particles of a viscoelastic medium according to any one of claims 1 to 8, for therapeutic soft tissue augmentation in a mammal, including man, wherein the majority by volume of said particles have an average particle size of from 1 to 5mm when present in a physiological salt solution, wherein said medicament is suitable for administration subcutaneously at the site of said mammal in need of therapeutic soft tissue augmentation according to any one of claims 15 to 23.