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 M C, 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 N E 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), U.S. Pat. No. 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 Ågerup 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 R S 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 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 displacement of the implant from the desired site of implantation.

It is also an object of the present invention to provide use of a viscoelastic 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.

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.

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 application of a pressure of 15-50 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, 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. 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 1 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.

