Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-04-20
2004-05-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S490000, C424S497000
Reexamination Certificate
active
06730324
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel room-temperature process for obtaining calcium phosphate, in particular hydroxyapatite, microspheres and coatings with encapsulated drugs, proteins, genes, DNA for therapeutical use. The coatings and microspheres are designed to perform a defined biological function related to drug delivery, such as gene therapy through gene delivery. A novel method for encapsulation, and subsequent controlled release of therapeutically active agents from such biofunctional coatings and microspheres is disclosed. Such coatings and microspheres are useful for side effects-free, long-term, targeted, controlled release and delivery of drugs, proteins, DNA, and other therapeutic agents.
BACKGROUND OF THE INVENTION
Rapid progress in the human genome project promises that diseases that could not be treated before can be curable in near future. The expectation is that the trial-and-error era of fighting illnesses by addressing the symptoms is coming to an end. Consequently, the issue of drug and gene release control becomes increasingly critical. Currently, many types of new drugs, or genes, have to be administered by daily injections, or even several times per day. An entirely new approach to drug delivery is therefore necessary to fully utilize the advantages of new drugs resulting from the genome project. Slow but steady release of drugs is sought in treatment of many diseases, from cancer and Parkinson's disease, to hormonal treatment of obesity where directly administered hormones reside in human body only for short period of time. In the past, polymeric materials have been used for drug delivery control and enjoyed substantial clinical success for certain drug systems. The need for alternative inorganic drug delivery systems, offering more flexibility in drug-carrier system selection, bioresorption and release control, hydrophobic/hydrophilic property control, and negligible side effects, is just emerging. Hydroxyapatite (HA) matrix for drug encapsulation, being already the principal inorganic component of bone, offers entirely new perspectives for drug delivery systems.
Hydroxyapatite Ceramics, Ca
10
(PO
4
)
6
(OH)
2
, belong to a large class of calcium phosphate (CaP) based bioactive materials used for a variety of biomedical applications, including matrices for drug release control [M. Itokazu et al Biomaterials, 19,817-819,1998; F. Minguez et al Drugs Exp. Clin. Res., 16[5], 231-235, 1990; W. Paul and C. P. Sharma, J. Mater. Sci. Mater. Med., 10, 383-388,1999]. Other members of the CaP family, such as dicalcium phosphate CaHPO
4
2H
2
O or tricalcium phosphate Ca
3
(PO
4
)
2
, have also been used for similar purposes. The CaP family of materials has been long recognized as having highest degree of biocompatibility with human tissue.
Calcium Phosphate Cements (CPC) were reported in a binary system containing tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrate (DCPA) [L. C. Chow et al. J. Dent Res., 63, 200,1984]. The CPC advantages of self-setting and apatitic phase, e.g. HA, as an end product led to applications such as bone replacements and reconstruction, and also drug delivery [M. Dairra, et al. Biomaterials, 19 1523-1527, 1998; M. Otsuka, et al. J. of Controlled Release 43(1997)115-122, 1997; Y. Tabata, PSTT, Vol.3, No.3, 80-89, 2000; M. Otsuka, et al. J. of Pharm. Sci. Vol.83, No.5, 1994]. CPC is typically formulated as a mixture of solid and liquid components in pertinent proportions, which react to form the apatite. The physicochemical reactions that occur upon mixing of the solid and liquid components are complex, but dissolution and precipitation are the primarily mechanisms responsible for the final apatite formation [C. Hamanish et al J. Biomed. Mat. Res., Vol.32, 383-389,1996; E. Ferandez et al J. Mater. Sci.Med.10,223-230, 1999]. The reaction pathway in most CPC systems does not lead to stoichiometric HA, but rather calcium-deficient Ca
10−x
(HPO
4
)
x
(PO
4
)
6−x
(OH)
2−x
, similar to that found in bone. The process parameters, such as Ca/P ratio, powder/liquid ratio, seeds concentration and type, nature of reagents, control the final properties, such as phase content, porosity, strength, setting time, phase transformation kinetics, and microstructure of CPC-derived hydroxyapatite (CPC-HA). Bermudez et al [J. Mat. Sci. Med. 4, 503-508,1993; ibid 5, 67-71, 1994] correlated the compressive strength of CPC vs starting Ca/P ratio in the systems of monocalcium phosphate monohydrate (MCPM) and calcium oxide. The optimum Ca/P ratio was found in a range of 1.25-1.45. Brown et al. [J. Am. Cerm. Soc. 74[5] 934-40,1991] found that the kinetics of HA formation at low temperatures in DCP/TTCP system are initially controlled by the surface area of the reactants, and eventually by diffusion. These process variables will be used in the present project to control crystallinity, and thus resorption and drug release rate from the HA microspheres.
Biomimetic Deposition of HA films at room temperature (BM-HA) was used for a variety of biomedical applications, including drug delivery [H. B. Wen et al, J. Biomed. Mater. Res., 41, 227-36,1998; S. Lin and A. A. Campbell, U.S. Pat. No. 5,958,430, 1999; D. M. Liu et al J. Mater. Sci. Mater. Med., 5, 147-153,1994; K. de Groot et al, J. Biomed. Mater. Res., 21, 1375-1381,1987]. This forming mechanism is driven by supersaturation of Ca
2+
and PO
4
3−
, under appropriate solution pH, where HA is the most stable phase. The apatitic crystals form through nucleation and growth, and may incorporate biologically active species, such as antibiotics, anti-cancer drugs, anti-inflammatory agents, etc. The deposition rates are however small for BM-HA, generally in the range of 0.05-0.5 &mgr;m/h, and high concentration dosage of drug is difficult to achieve. Therefore, stand-alone BM-HA is not suitable if the goal is to form films in excess of 1 &mgr;m, but may be appropriate as an additional encapsulating film, on top of the porous HA structure saturated with the drug material. This is especially critical for orthopedics where high concentration of antibiotics is required at bone-HA interface to prevent acute inflammation in early after-operation stages. Furthermore, the physiological solutions for BM-HA formation are naturally water-based, which makes impossible to encapsulate hydrophobic bioactive agents into BM-HA coatings.
Sol-Gel Deposition of HA (SG-HA) films at elevated temperatures (375-500° C.) was disclosed previously by D. Liu and T. Troczynski in U.S. patent application Ser. No. 09/563,231, filed May 2, 2000, the subject matter of which is incorporated herein by reference. Sol-gel (SG) processing of HA allows molecular-level mixing of the calcium and phosphor precursors, which improves chemical homogeneity of the resulting calcium phosphate. The versatility of the SG method opens an opportunity to form thin film coatings in a simple, mild, relatively low-temperature process. The crystallinity of the calcium phosphate phase obtained through the novel inventive process by D. Liu and T. Troczynski can be enhanced by appropriate use of water treatment during processing. Variation of Ca/P ratio in the sol-gel precursor mix allows one to obtain other than calcium phosphate phases, for example, hydroxyapatite, dicalcium phosphate, tricalcium phosphate or tetracalcium phosphate. The use of SG-HA thin (<1 &mgr;m) dense highly crystalline films to nucleate and grow thick (>10 &mgr;m) CPC-HA porous, low-crystallinity (amorphous) films for drug encapsulation and release is hereby disclosed.
Problems With Drug Delivery in Vivo are related to toxicity of the carrier agent, the generally low loading capacity for drugs as well as the aim to control drug delivery resulting in self-regulated, timed release. With the exception of colloidal carrier systems, which support relatively high loading capacity for drugs, most systems deliver inadequate levels of bioactive drugs. In terms of gen
Liu Dean-Mo
Troczynski Tomasz
Yang Quanzu
Oyen Wiggs Green & Mutala
Pilliam Amy E
The University of British Columbia
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