Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined...
Reexamination Certificate
1998-10-29
2001-09-04
Chan, Christina Y. (Department: 1644)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
C424S572000, C514S021800, C514S801000
Reexamination Certificate
active
06284284
ABSTRACT:
INTRODUCTION
The present invention relates to compositions and methods for the treatment and repair of soft tissue and skin defects such as wrinkles and scars. More particularly, the invention relates to an injectable composition of human extracellular matrix components and methods of preparing and using same. The injectable preparation is obtained from three-dimensional living stromal tissues that are prepared in vitro.
BACKGROUND OF THE INVENTION
The idea of using an injectable material for soft tissue augmentation and repair developed soon after the invention of the hypodermic needle. Various products have been injected into the human body for correction of soft tissue and skin defects including paraffin, petrolatum, vegetable oils, lanolin, bees wax, and silicone. Injectable liquid silicone has been used extensively, however, due to long term side effects, such as nodules, recurring cellulitis and skin ulcers which are now being followed more closely, the use of injectable silicone is on the decline. Further, in the State of Nevada it is a felony to use injectable silicone in a human. Orange, Skin and Allergy News (1992) Vol.23, No.6, pg. 1. More recently, bovine collagen has gained widespread use as an injectable material for soft tissue augmentation. Collagen is the principal extracellular structural protein of the animal body. At least fourteen types of mammalian collagen have been described. The common characteristic amongst them is a three stranded helix, consisting of three polypeptide chains, called alpha-chains. All alpha-chains have the same configuration, but differ in the composition and sequence of their amino acids. Although this leads to different types of alpha-chains, however, they all have glycine at every third position in the amino acid sequence. The glycine at every third position allows for the helical structure of the alpha-chains. Type I collagen is composed of two alpha
1
-chains and one alpha
2
-chain and is the principal extracellular material of skin, tendon and bone. When clinicians mention “collagen”, they are usually referring to type I collage n. See Table I, infra, for a detailed listing of collagen types I-V and in which tissues they are found.
Collagen has been used as an implant material to replace or augment hard or soft connective tissue, such as skin, tendon, cartilage, bone and interstitium. Additionally, collagen implants have been used for cosmetic purposes for a number of years since collagen can help cellular ingrowth at the placement site. Early collagen implants were often solid collagen masses which were cross-linked with chemical agents, radiation or other means to improve mechanical properties, decrease immunogenicity and/or increase resistance to resorption. The collagen utilized was in a variety of forms, including cross-linked and non-cross-linked fibrillar collagens, gelatins, and the like and sometimes was combined with various other components, such as lubricants, osteogenic factors and the like, depending on use. A major disadvantage of solid cross-linked collagen implants is the requirement for surgical implantation by means of incision. In addition, lack of deformability and flexibility are other disadvantages of solid collagen implants.
Oliver et al., Clinical Orthopaedics & Related Research (1976) 115:291-302; Br. J. Exp. Path. (1980) 61:544-549; and Conn. Tissue Res. (1981) 9:59-62 describe implants made by treating skin with trypsin followed by cross-linking with an aldehyde. The resulting solid collagen implants were reported to maintain their original mass after prolonged implantation. A main problem with such solid implants is that they must be implanted surgically. Other disadvantages are that they are not as deformable as injectable implants and residual glutaraldehyde may cause the implant to lose its flexibility due to continuing cross-linking in situ.
Schechter, et al., Br. J. Plas. Surg. (1975) 28:198-202 disclose glutaraldehyde cross-linked skin that was soaked in L-alanine after cross-linking. The article postulates that the exposure of the skin to L-alanine blocked residual reactive groups of the aldehyde, thereby preventing the release of toxic molecules generated by such groups.
An alternative to surgically implanted solid collagen material is disclosed in U.S. Pat. Nos. 3,949,073. 3,949,073 describes the use of atelopeptide solutions of bovine collagen as an injectable implant material for augmenting soft tissue. According to the patent, the bovine collagen is reconstituted before implantation and forms a fibrous mass of tissue when implanted. The patent suggests adding particles of insoluble bovine collagen microfibrils to control the shrinkage of the fibrous mass formed at the augmentation site. The commercial embodiment of the material described in the patent is composed of reconstituted atelopeptide bovine collagen in saline that contains a small amount of local anesthetic. While effective, the implant shrinks in volume after implantation due primarily to absorption of its fluid component by the body. Thus, if volume consistency is essential, an additional injection or injections of supplemental implant material is required. This specific composition has many serious drawbacks, e.g., the collagen is from a bovine source, not human, and the preparation process is not only lengthy and expensive but also requires the addition of microfibrils.
U.S. Pat. No. 4,424,208 describes an injectable dispersion of cross-linked atelopeptide bovine collagen and reconstituted atelopeptide bovine collagen fibers in an aqueous carrier which exhibited improved volume consistency over the material of U.S. Pat. No. 3,949,073.
U.S. Pat. No. 4,582,640 discloses an improved injectable implant over U.S. Pat. Nos. 3,949,073 and 4,424,208 in which the improvement consists of improved volume consistency and resistance to physical deformation, improved injectability as compared to the dispersion of U.S. Pat. No. 4,424,208 and that the bovine collagen contains only a single physical form of collagen as compared to the two physical forms found in U.S. Pat. No. 4,424,208.
U.S. Pat. No. 4,803,075 describes bovine collagen compositions including a lubricant material to enhance injectability through narrow diameter needles for soft tissue repair.
Despite the advantages and overall usefulness of the injectable collagen implant materials disclosed above, problems associated with producing and injecting the materials have been encountered. For example, for soft tissue repair, suspensions of fibrillar collagen have often been used by injecting the composition to a treatment site through a fine gauge needle. The use of fibrillar collagen as the primary matrix material in injectable soft and hard tissue implant compositions has several limitations. The preparation of fibrillar collagen suitable for human use is relatively time consuming and expensive. In particular, the complete removal of contaminating and potentially immunogenic substances to produce atelocollagen is a relatively complex and expensive procedure. Moreover, the persistence, shape retention, cohesiveness, stability, elasticity, toughness and intrudability of the fibrillar collagen compositions are not optimal.
In addition to the problems associated with producing and injecting the collagen implant materials, problems with the actual use of the above mentioned patented injectable implants are also abundant. For instance, since the above patented injectables derive collagen from xenogeneic sources, usually bovine collagen, the collagen must be modified to reduce its immunogenicity. Even with modified collagen, the implant material is still quite immunogenic to which some people are either already naturally allergic or develop an allergic reaction over time to the bovine collagen. Due to these allergic reactions the injectable collagen implants described above cannot be given to many people and others are limited to receiving only three injections per year. Severe allergic reactions include symptoms of rheumatoid arthritis, while less severe reactions include redness and
Advanced Tissue Sciences Inc.
Chan Christina Y.
Clemens Karen
Pennie & Edmonds LLP
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