Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-01-15
2002-11-19
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C514S944000, C516S105000
Reexamination Certificate
active
06482435
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to temperature-sensitive polymers for the sustained delivery of pharmacological agents and, more particularly, to poloxamers comprising suspensions of native macromolecular polypeptide agents.
2. Description of the State of the Art
Recent years have seen major advances in recombinant DNA techniques and consequently the proliferation of many protein pharmaceuticals available for a variety of therapeutic needs. Indeed, proteins or polypeptides constitute the largest class of drugs currently being considered for FDA approval. However, the therapeutic and commercial potential of polypeptide drugs will only be realized if these advances are accompanied by formulation designs leading to effective administration and stability.
Proteins are large organic molecules or macromolecules made up of amino acid residues covalently linked together by peptide bonds into a linear, unbranched polypeptide chain with relative molecular mass ranging from a few thousand to millions. The useful properties of proteins as drugs depend upon the polypeptide chain adopting a unique three-dimensional folded conformation, that is, the tertiary structure of the protein. It is this unique folding that is responsible for the protein being highly selective in the molecules it will recognize. However, the ability to maintain a unique three-dimensional structure is precisely one of the obstacles that makes the use of polypeptides in human and animal diseases fraught with problems.
Traditionally, the most widely used method of administration of therapeutic agents is by the oral route. However, such delivery is not feasible, in the case of macromolecular drugs, as they are rapidly degraded and deactivated by hydrolytic enzymes in the alimentary tract. Even if stable to enzymatic digestion, their molecular weights are too high for absorption through the intestinal wall. Consequently, they are usually administered parenterally; but, since such drugs often have short half-lives in vivo, frequent injections are required to produce an effective therapy. Unfortunately, while the parenteral route is the most efficient means of drug introduction, this route has severe drawbacks in that injections are painful; they can lead to infection; and they can lead to severe vascular problems as a result of repeated intravenous injections.
For these reasons, biodegradable polymer matrices have been considered as sustained release delivery systems for a variety of active agents or drugs. Once implanted, the matrix slowly dissolves or erodes, releasing the drug. An alternative approach is to use small implantable pumps, which slowly extrude the drug and matrix components, which dissolve after contacting body fluids. With both systems it is crucial that the drug remain evenly distributed throughout the matrix since heterogeneous distribution of the drug (e.g., formation of large clumps and voids) could lead to erratic dosing. Furthermore, both systems require polymers that remain somewhat fluid so that they can be easily manipulated prior to implantation or loading into a device.
The use of polymers as solid implants and for use in small implantable pumps for the delivery of several therapeutic agents has been disclosed in scientific publications and in the patent literature. See, for example, Kent, et al., “In vivo controlled release of an LHRH analog from injected polymeric microcapsules”,
Contracept, Deliv. Syst.,
3:58 (1982); Sanders, et al., “Controlled release of a luteinizing hormone releasing hormone analogue from poly (d, l-lactide-co-glycolide)—microspheres”,
J. Pharmaceut. Sci.,
73:1294-1297 (1984); Johnston, T. P., et al., “Sustained delivery of Interleukin-2 from a poloxamer 407 gel matrix following intraperitoneal injection in mice”,
Pharmaceut. Res.,
9(3):425-434 (1992); Yolks, et al., “Timed release depot for anti-cancer agents II”,
Acta Pharm. Svec.,
15:382-388 (1978); Krezanoski, “Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes”, U.S. Pat. No. 4,474,752. However, the polymers having the greatest potential for use in the delivery of protein drugs would exhibit reverse thermal gelation and have good drug release characteristics.
There exists a class of block copolymers that may be generically classified as polyoxyethylene-polyoxypropylene condensates, namely Pluronic polyols, or poloxamers. They are formed by the condensation of propylene oxide into a propylene glycol nucleus followed by the condensation of ethylene oxide into both ends of the polyoxypropylene base. The polyoxyethylene hydrophilic groups on the ends of the molecule are controlled in length to constitute anywhere from 10 percent to 80 percent by weight of the final molecule.
Poloxamers, which have the ability to gel as a function of temperature and polymer concentration, may be represented emperically by the formula:
HO(C
2
H
4
O)
b
(C
3
H
6
O)
a
(C
2
H
4
O)
b
H (I)
wherein a and b are integers such that the hydrophobe base represented by (C
3
H
6
O)
a
has a molecular weight ranging from about 900 to 4,000, as determined by hydroxyl number; and the polyoxyethylene chain consisting of at least 60 percent to 70 percent by weight of the copolymer, and the copolymer having a total average molecular weight ranging from about 4,000 to 15,000. Table 1, below, references the minimum concentrations of various poloxamers necessary to form a gel in water at room temperature.
TABLE 1
Poloxamer*
Molecular Weight
Minimum Concentration
Pluronic ® F-68
8,400
50%-60%
Pluronic ® F-88
11,400
40%
Pluronic ® F-108
14,600
30%
Pluronic ® F-127
12,600
20%
*Poloxamers are commercially available under the referenced trademarks through the BASF Corporation, Parsippany, N.J.
Poloxamers of low molecular weight, i.e., below 10,000 MW, do not form gels at any concentration in water.
While poloxamers, and more specifically Pluronic® F-127 or Poloxamer 407, have been used to deliver nonpeptidic drugs as well as biologically active proteins, see U.S. Pat. Nos. 4,100,271 and 5,457,093, respectively, sustained delivery of biologically active macromolecules for weeks or months has not been possible for reasons that are two-fold. First, previous references which disclose the incorporation of proteins in a Pluronic® matrix only disclose solutions of a protein, with concentrations less than approximately 2 mg/ml and second, formulation approaches used to incorporate proteins into polymeric systems often result in irreversible inactivation of the proteins because of the presence of organic solvents, pH changes, and thermal effects. Consequently, prior references which teach the use of poloxamers as pharmaceutical vehicles for the delivery of proteins have suffered two serious limitations; (i) low initial concentrations of protein are used, and (ii) an unacceptable percentage of the protein loses its biological activity during use or storage. These two limitations have a direct impact on the ability to produce a polypeptide drug delivery system which can be shelved for long periods of time prior to usage and administer controlled dosages of protein for a period of weeks or more preferably months. Furthermore, degraded proteins can have reduced efficacy as a drug, and can also elicit adverse reactions, such as sensitization and adverse immune response.
There is still a need, therefore, for a polypeptide drug delivery device or composition having high concentrations of fully native macromolecular polypeptides which may be regularly released over a long period of time.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to provide a polypeptide drug delivery system.
It is a further object of this invention to provide a polypeptide drug delivery device or composition having protein or peptide concentrations greater than 5 mg/ml.
It is an additional object of the present invention to incorporate protein stabilizers into the drug delivery device.
Additional
Carpenter John F.
Manning Mark C.
Stratton Lewis P.
Sheridan & Ross P.C.
University Technology Corporation
Webman Edward J.
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