Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Phosphorus or phosphorus compound
Reexamination Certificate
1996-10-16
2003-04-01
Dodson, Shelley A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Phosphorus or phosphorus compound
C423S308000, C423S311000, C514S002600
Reexamination Certificate
active
06541037
ABSTRACT:
BACKGROUND OF THE INVENTION
Much research in the area of biopharmaceutics is directed toward the development of effective implantable drug delivery vehicles. Such vehicles must be biocompatible and also must be capable of protecting the activity of the biologically active agent they are intended to deliver. Many biologically active agents are labile and easily lose activity when they are incorporated into a delivery material. Preservation of protein activity has posed particularly difficult problems.
Calcium phosphate ceramics have been studied as potential drug delivery systems due to their well known biocompatibility and their affinity for protein reagents (see, for example, IJntema et al.,
Int. J. Pharm
. 112:215, 1994; Itokazu et al.,
J. Orth. Surg
. 2:47, 1994; Shinto et al.,
J. Bone Joint Surg
. 74-B:600, 1992; Uchida et al.,
J. Orth. Res
. 10:440, 1992). However, the reactions employed to produce known calcium phosphate ceramic materials typically require elevated temperatures and/or pressures, and also require the presence of acids or bases. Because most biologically active agents would be destroyed by one or more of the conditions required to produce the ceramic, the biologically active agents can only be loaded in after the material is produced, which can limit the amount and type of agent that can be delivered.
Also, although a number of calcium phosphate materials have been referred to as “resorbable”, such compounds, usually comprising or derived from tricalcium phosphate, tetracalcium phosphate or hydroxyapatite are in fact only weakly resorbable. Of the group, the tricalcium phosphate compounds have been demonstrated to be the most resorbable and, after many years of study, they are still not widely used in clinical settings. The tricalcium phosphates are known to have lengthy and somewhat unpredictable resorption profiles, generally requiring in excess of one year for resorption. Unless steps are taken to produce extremely porous or channeled tricalcium phosphates, these compounds are not replaced by bone. Recent studies have lead to the conclusion that the “biodegradation of TCP, which is higher than that of [hydroxyapatite], is not sufficient” (Berger et al.,
Biomaterials
, 16:1241, 1995).
Tetracalcium phosphate and hydroxyapatite derived compounds are also only weakly resorbable. Published reports of tetracalcium phosphate fillers generally describe partial resorption over long periods of time. For example, as reported by Horioglu et al., it is not uncommon for such materials to require 30 months for 80% resorption (
Soc. for Bionatenals
, pg. 198, Mar. 18-22, 1995). Also, many reports that describe “resorption” of calcium phosphate materials do not actually demonstrate resorption because the authors do not rule out, for example, migration of the vehicle from the implant site (see, for example, IJntema et al., supra).
There remains a need for the development of a drug delivery vehicle that is biocompatible, fully resorbable, and not detrimental to drug activity. Preferably, the resorption rate of the material should be modifiable in known ways. Also, the material should be easy to manufacture, preferably using mild reaction conditions.
DEFINITIONS
“Amorphous”—By “amorphous” as that term is used here, it is meant a material with significant amorphous character. Significant amorphous character contemplates greater than 75% amorphous content, preferably greater than 90% amorphous content, and is characterized by a broad, featureless X-ray diffraction pattern. It is recognized that a small degree of crystallinity may exist in the material. However, for the amorphous precursor materials of the present invention, it is preferable that the degree of crystallinity be less than that desired in the product material.
“Bioactive”—“Bioactive” refers to a material that induces hard tissue formation in and about the implant. When implanted in soft tissue, the bioactivity may also require the presence of a growth or trophic factor, or the seeding of the implant with a hard tissue forming cell type.
“Biocompatible ”—The term “biocompatible”, as used herein, means that the material does not elicit a substantial detrimental response in the host. There is always concern, when a foreign object is introduced into a living body, that the object will induce an immune reaction, such as an inflammatory response that will have negative effects on the host. For example, although hydroxyapatite is generally considered to be “biocompatible”, significant inflammation and tissue necrosis have been observed when crystalline hydroxyapatite microcarriers are inserted intramuscularly in animals (see, for example, IJntema et al.,
Int. J. Pharm
112:215 (1994)).
“Bioresorbable”—“Bioresorbable” refers to the ability of a material to be resorbed in vivo. “Full” resorption means that no significant extracellular fragments remain. The resorption process involves elimination of the original implant materials through the action of body fluids, enzymes or cells. Resorbed calcium phosphate may, for example, be redeposited as bone mineral, or by being otherwise reutilized within the body, or excreted. “Strongly bioresorbable”, as that term is used herein, means that at least 80% of the total mass of material implanted intramuscularly or subcutaneously is resorbed within one year. In preferred embodiments of the invention, the strongly resorbing PCA calcium phosphate is characterized in that, when at least 1 g (preferably 1-5 g) of PCA material is implanted at a subcutaneous or intramuscular site, at least 80% of the material is resorbed within one year. In more preferred embodiments, the material will be resorbed within nine months, six months, three months, and ideally one month. Furthermore, particularly preferred materials are characterized in that they can be fully resorbed in the stated time periods. For the purpose of this disclosure, “weakly” resorbable means that less than 80% of the starting material is resorbed after one year.
“Effective Amount”—An effective amount of a biologically active agent is an amount sufficient to elicit a desired biological response.
“Hardening”—“Hardening” refers to the process by which the hydrated precursor is transformed into a hardened PCA material. The PCA material is considered to be “hardened” when it is a substantially non-formable solid. Such a hardened PCA material has minimal compressibility and tends to undergo plastic as opposed to elastic deformation.
“Hydrated precursor”—The term “hydrated precursor”, as used herein, refers to the paste or putty formed by hydration of the dry PCA precursors in the presence of a limited amount of aqueous solution (i.e., less than approximately 1 mL aqueous solution/1 g precursor powder). The hydrated precursor may comprise both reactants and products, in various combinations, depending on the extent to which the conversion has progressed. Both the “injectable” and “formable” PCA precursor pastes described herein are hydrated precursors. Preferred “injectable” hydrated precursors have a consistency appropriate for delivery through an 18 gauge needle.
“Poorly crystalline apatitic calcium phosphate”, “PCA calcium phosphate” and “PCA material”, as those terms are used herein, describe a synthetic poorly crystalline apatitic calcium phosphate. The PCA material is not necessarily restricted to a single calcium phosphate phase provided it has the characteristic XRD and FTIR pattern. A PCA calcium phosphate has substantially the same X-ray diffraction spectrum as bone. The spectrum is generally characterized by only two broad peaks in the region of 20-35° with one centered at 26° and the other centered at 32°. An additional broad shoulder occurs at approximately 2&thgr;=29 and another may be present at approximately 2&thgr;=33.6. Absent from the spectra are any additional sharp peaks or sharp shoulders characteristic of crystalline hydroxyapatite occurring in the range of 2&thgr;=27-34. In particular, there are no sharp peaks or shoulders corresponding to Miller's Indices for 210, 112,
Aiolova Maria
Lee Dosuk D.
Rey Christian
Dodson Shelley A.
Etex Corporation
Hale and Dorr LLP
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