Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-04-16
2003-07-29
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S450000, C623S016110
Reexamination Certificate
active
06599517
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the field of implant materials for restoring bone tissues in humans or animals. More specifically the invention relates to a new, easily and consistently applicable composition suitable for restoring bone tissue in a human or animal body, to a method of preparing said composition, to uses of the same as well as to an implant product obtainable from said composition.
BACKGROUND OF THE INVENTION
The repair and reconstruction of osseous defects have long been a serious challenge to the skills of orthopedic and maxillofacial surgeons.
In order to restore form and function to patients, repairing bone defects presently involves several surgical techniques. However, although effective in many cases, the existing technology has numerous difficulties and disadvantages.
Therefore the implantation of materials of different types in the human or animal body in order to replace bone portions which have been traumatized or which have deteriorated due to diseases is steadily increasing. In order to eliminate the risk of having immunological or infectious diseases and to avoid operations on several sites, different synthetic materials have come into use within this technical field. As examples of suitable materials used for said purpose there can be mentioned minerals and ceramics such as tricalcium phosphate and calcium aluminate. Especially preferred materials are, however, materials having a chemical composition and crystal structure similar to those of the materials that are built up by the living organism, such as calcium hydroxy-apatite. One synthetic material of this type which has come into use for restoring bone tissue is the mineral calcium hydroxyapatite and is available both as blocks of different shapes and granules of different sizes.
Commercial hydroxyapatite is supplied by many producers. Thus, for instance, hydroxyapatite of the above-mentioned formula is manufactured by Asahi Optical Co., Ltd., Tokyo, Japan, Interpore Int. Irvine, Calif., USA, and Impladent Ltd., Holliswood, N.Y., USA. The material is available both as resorbable and as non-resorable hydroxyapatite granules/particles for different applications.
In most cases the above-mentioned granules or particles are mixed with blood or a physiological saline solution in order to obtain a mass that is easier to apply to the desired site of the bone, when applying said granules or particles to the bone. A major drawback to this materia or technique is, however, that such a mass is not easily properly confined within the bone cavity referred to. Furthermore, when the mass has been applied to the bone, blood that may come from adjacent bleeding portions of the body or any other secreted body fluid will dilute the particulate mass and may even carry away the material from the site of application.
Attempts to solve these problems have been made, as is for instance disclosed by Alper G. et al. in The American Journal of the Medical Sciences, December 1989 (298): 371-376. However, said reference clearly shows that generally a moldable hydroxyapatite system based on phospholipid and added stearic acid does not stimulate new bone formation or conduct bone growth but rather demonstrates a decrease in bone formation.
Furthermore, since liposomes, which are spherical particles consisting of closed bilayers with water inside as well as outside thereof, have a membrane structure similar to matrix vesicles, Huang et al. have suggested, in Kao Hsiung I Kaohsiung J.Med.Sci. 1997, 13:213-228, that negatively charged liposomes might improve the nucleation process for new bone formation. This concept was tested in a mandibular defect of miniature swine but was not confirmed. Thus, they found that when comparing the bone development of pure calcium phosphate with liposome-coated calcium phosphate the pure implanted material had better and more mature bone tissue development and that the amount of bone tissue was greater than for the implanted material coated with liposomes.
Phospholipids have also been used to produce sustained release formulations of drugs from ceramic granules as is e.g. disclosed in Japanese Patent No. 2,198,560. Antibiotic-loaded hydroxyapatite has been of especial interest since local infections of the operating site is a potential complication. (Df. Yamamura K et al., Journal of Biomedical Materials Research, Vol. 26, 1053-1064 (1992), and Shinto Y. et al., J. Bone Joint Surg., 1992 (74):600-604).
Finally, as concerns implant compositions, reference is also made to EP 0 429 419, which discloses a system where calcium phosphate, and especially hydroxyapatite, is used as a bone tissue substitute material. However, in said case no phospholipid is used but rather a monoglyceride as the basis for the carrier. Furthermore, as in all other cases represented by the prior art, the carrier is not of the same nature as the carrier according to the present invention. Thus, as will be described below the composition according to the present invention as based on a lamellar liquid crystalline phase used as such for the bone formation step. Contrary thereto, EP 0429 419 relies on the use of a phase conversion from an L2-phase into a harder cubic liquid crystalline phase or reversed hexagonal liquid crystalline phase for the bone formation step. In the present case the composition of the lamellar liquid crystalline phase is such that no phase conversion takes place if adding further water. Rather, it is even possible that addition or presence of body fluid after the composition has been implanted promotes the dispersion of the lamellar liquid crystalline phase and the removal of the same from the implant site to thereby enhance the healing process by exposing a bioactive hydroxy-apatite surface to the cells.
The primary object of the present invention is to overcome the drawbacks referred to above and to provide an implant material which can be easily and consistently be applied to the desired site of action, i.e. where the bone tissue restoration is to be made. More specifically, this means that the new implant material according to the present invention is capable of resisting dilution and any forces tending to carry away the material from the place of application.
Furthermore, the bone restoration properties as well as the biocompatibility of the new composition according to the present invention has been found to be outstanding as compared to other, previously known systems.
GENERAL DISCLOSURE OF THE INVENTION
According to the present invention it has been found that the objects referred to above can be achieved by providing a composition wherein a solid calcium phosphate is used as a biocompatible bone tissue substitute material which is distributed in a lamellar liquid crystalline phase comprising at least one phospholipid and water or other aqueous liquid as a bioacceptable carrier therefor. Thus, by using a calcium phosphate, and especially hydroxyapatite, as the main or only bone tissue substitute material in combination with phospholipid(s) in the form of a specific phase, i.e. a lamellar liquid crystalline phase, an implant composition is achieved, the properties of which are outstanding relative to previously known compositions in this field.
In addition to what has been disclosed above concerning advantages of the present invention, it could be added that other previously tested gel systems show several disadvantages. Thus, for instance a water-based gel-like hyaluronic acid is rapidly dehydrated, which means that the consistency thereof varies under the use thereof. This in turn means than it is much more difficult to shape and handle than the composition according to the present invention. The use of proteins like collagen from animals can impart undesirable immunologic reactions, while the use of two component gel systems is a complicated procedure requiring the mixing and curing of two ingredients during a limited time.
Moreover, it should be noted that the composition according to the present invention has been found to show a high amount of newly formed bone while sta
Danielsen Nils
Ljusberg-Wahren Helena
Burns Doane , Swecker, Mathis LLP
Camarus AB
Kishore Gollamudi S.
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