Injectable and swellable microspheres for dermal augmentation

Details Injectable and swellable microspheres for dermal augmentation Injectable and swellable microspheres for dermal augmentation

2002-08-19

2004-09-14

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S400000, C424S423000, C424S489000, C424S501000

Reexamination Certificate

active

06790456

ABSTRACT:

1. FIELD OF INVENTION
The present invention relates to dermal augmentation, particularly for the treatment of skin contour deficiencies, using injectable compositions comprising swellable hydrophilic microspheres.
2. BACKGROUND OF THE INVENTION
Damage to the skin due to aging, environmental exposure to the sun and other elements, weight loss, child bearing, disease such as acne and cancer, and surgery often results in skin contour deficiencies and other skin anomalies. In order to correct contour deficiencies and other anomalies of the skin, people often resort to cosmetic surgery, such as face lifts and skin tucks. Cosmetic surgery, however, has several drawbacks, in addition to the high cost associated with it. It is usually an invasive and risky procedure, having the potential of leaving scars in areas of operation and affecting normal biological and physiological functions. Furthermore, cosmetic surgery is often a limited option, available only for certain skin deficiencies.
In addition to cosmetic surgery, various other methods are used to remove or ameliorate the deficiencies with different levels of success. The use of injectable material for soft tissue augmentation is a method often used. The advantage of using hypodermic needles as a delivery device for dermal augmentation reflects the advantages of using hypodermic needles in general: easy, precise and, usually, non-invasive deliveries. Yet, the requirement for such use is also quite strict: the material to be delivered must be deliverable through the needles, which means the material must be able to easily pass through the hollow centers of the needles.
One method of dermal augmentation using injectable material is liquid or semi-liquid injections, usually containing collagen. The best known example is a collagen preparation manufactured by Collagen Corporation (now part of Inamed Corporation) and marketed by C. R. Bard. However, collagen is a naturally occurring substance which the body may enzymatically degrade and eliminate over time, thus requiring repeat treatments. Also, collagen may be displaced within the tissue in which it was originally injected, thereby reducing or eliminating the intended dermal augmentation effect. Collagen is also digested directly (biochemically), through macrophages, through the lymphatic system, or by other means. Even more alarming from a cosmetic perspective, collagen may move from the initial site of injection, causing unsightly bumps and bulges under the skin at undesired locations. See, e.g., Millikan, Long Term Safety and Efficacy with Fibrel in the Treatment of Cutaneous Scars,
J Dermatol Surg Oncol,
15:837-846 (1989).
Injection of liquid silicone has also been used extensively. However, due to long term side effects, such as nodules, recurring cellulitis, and skin ulcers, the use of injectable silicone is on the decline. See, e.g., Edgerton et al., Indications for and pitfalls of soft tissue augmentation with liquid silicone,
Plast. Reconstr. Surg,
58:157-163 (1976).
Solid microparticles have also been used for the correction of skin deficiencies. For example, carbon particles, silicone particles, TEFLON paste, collagen beads and polymethylmethacrylate spheres, have been used with disappointing results due to, inter alia, adverse tissue reactions, biological degradation and migration from the initial implantation location. U.S. Pat. No. 5,451,406 discloses an injectable biocompatible composition for tissue augmentation comprising a plurality of discrete substrate particles with a carbon coating in a carrier. The substrate particles in the '406 patent are metallic substrate such as stainless steel, titanium, titanium alloy, and their oxides.
The problems associated with rigid and non-deformable particles, such as metal particles, carbon particles and silicone particles, in treating skin deficiencies are that they are either too fragile or too large to be injected, or too small and are digested or eliminated by the body. Therefore, such particles all have one or more of the following limitations: (i) too large to be injected through a 30 gauge or smaller needle; (ii) particles of irregular shape clump together, making injection difficult; (iii) particles are too fragile, resulting in breakage during injection and digestion of the residues; (iv) injected particles are too small and are digested by macrophages or other components of the lymphatic system; and (v) injected particles are displaced as they do not adhere to the surrounding cells.
Injectable deformable particles, such as TEFLON particles, have also been used for tissue augmentation, but results are also unsatisfactory. Such particles do not stay at the site of injection as they are deformed during and after injection, resulting in sliding within the tissue. They also do not return to their original shape, resulting in digestion by the body because their diameters become smaller during the injection process. For example, U.S. Pat. No. 5,007,940 discloses injecting deformable nonbiodegradable hydrogels with a lubricious surface into the brain tissues. Because of the nature of the hydrogels, the material injected has a risk of sliding of being carried away by the venous blood to central parts of the body, resulting in both less effective tissue augmentation and adverse effects to the body.
U.S. Pat. No. 5,633,001 discloses a biocompatible composition for tissue augmentation comprising a pseudoplastic polymer carrier (e.g., glucose amine glucans, hydroxy ethyl cellulose, carboxy methyl cellulose, xanthan gum, and alginates) and a water insoluble, biocompatible and biodegradable tissue augmenting substance comprising a dextranomer.
It is clear that there is still a great need for a safe, biocompatible, stable and effective method of dermal augmentation for the treatment of skin deficiencies. There is also a need for stable and biocompatible injectable compositions for dermal augmentation.
3. SUMMARY OF THE INVENTION
The present invention provides injectable compositions comprising swellable microspheres and method of using the injectable compositions to perform dermal augmentation, particularly for treatment of skin contour deficiencies, in a mammal. The composition is injectable through 30 gauge or smaller needles and the microspheres are not capable of being eliminated by macrophage (digested) or other elements of said mammal's immune system after injection.
The microspheres of the present invention are highly water absorbing and capable of swelling to many times of their original sizes under certain conditions. The microspheres of the present invention generally comprise crosslinked polymers. Preferably, the microspheres comprise sodium acrylate polymer, acrylamide polymer, acrylamide derivative polymer or copolymer, sodium acrylate and vinyl alcohol copolymer, vinyl acetate and acrylic acid ester copolymer, vinyl acetate and methyl maleate copolymer, isobutylene-maleic anhydride crosslinked copolymer, starch-acrylonitrile graft copolymer, crosslinked sodium polyacrylate polymer, crosslinked polyethylene oxide, or mixtures thereof. These microspheres are capable of swelling upon contacting with medium resembling the properties of physiological fluids, thus allowing the microspheres to secure themselves into position after injection into the body. Furthermore, the microspheres are substantially spherical and can be easily calibrated so that their sizes can be accurately determined. The microspheres of the invention have diameters from about 10 to about 400 &mgr;m before swelling. Preferably, before swelling, the diameters of the microspheres are from about 10 to about 200 &mgr;m and, most preferably, from about 10 to about 120 &mgr;m. After injection and swelling, the microspheres have average diameters larger than about 40 &mgr;m, preferably larger than about 50 &mgr;m and, more preferably, larger than about 70 &mgr;m.
In a preferred embodiment of the present invention, the microspheres further comprise cell adhesion promoters or cells on at least a portion of their surfaces. The cells are preferably aut

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