Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
1999-05-28
2002-11-19
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S002600, C514S964000, C424S484000, C424S489000
Reexamination Certificate
active
06482864
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a sustained-release preparation comprising a physiologically active polypeptide and a method for production thereof.
BACKGROUND ART
It is known that physiologically active polypeptides or their derivatives exhibit a variety of pharmacological activities in vivo. Some of these have been produced on a large scale by utilizing
Escherichia coli,
yeasts, animal cells or host animals such as goat and hamsters due to developed genetic engineering and cell technology, and put to medicinal use. However, these physiologically active polypeptides must be frequently administered because of the generally short biological half-life. The repeated injection put a significant physical burden on patients.
For instance, growth hormone (hereafter sometimes referred to as GH), a representative hormone which is originally produced and secreted in the anterior portion of the pituitary gland, is a physiologically active polypeptide having widely diverse physiological activities such as promotion of growth in the body, metabolism of glucose and lipids, anabolism of protein, and cell proliferation and differentiation. And GH has been recently produced on a large scale by utilizing
Escherichia coli
in genetic recombination technology field, and put to medicinal use clinically and worldwidely. However, GH must be frequently administered in order to maintain an effective blood concentration because of the short biological half-life. Especially, in the case of pituitary dwarfism, a daily subcutaneous administration to infants or young patients over a long period of time ranging from a few months to 10,years or more is the practical administration.
JP-A 3055/1996 (EP-A 633020) discloses a method for producing a sustained-release preparation which comprises permitting a water-soluble polypeptide to permeate into a biodegradable matrix comprising a biodegradable polymer and a metal salt of a fatty acid in an aqueous solution, and sustained-release microcapsules prepared by this method.
JP-A 217691/1996 (WO96/07399) discloses the production of a water-insoluble or slightly water-soluble polyvalent metal salt by using a water-soluble peptide type of physiologically active substance and an aqueous solution of zinc chloride, etc., and a method of producing a sustained-release preparation containing this salt and a biodegradable polymer.
WO 94/12158 discloses addition of a polymer erosion rate modulating agent such as zinc hydroxide in an amount of 0.1 to 30% (w/w) relative to the polymer into a polymer solution, as a method for producing a sustained-release preparation comprising human GH (hereafter sometimes referred to as hGH) and biodegradable polymer. This publication further discloses a method for producing microcapsules as porous particles by spraying an organic solvent solution of hGH and a polymer into liquid nitrogen, with biological activity retained.
WO 92/17200and Nature Medicine, Vol. 2, p. 795 (1996) disclose a method for producing a sustained-release preparation by using a zinc salt of human GH.
WO 95/29664 discloses a method for producing sustained-release microcapsules which comprises the steps of dispersing a metal salt such as zinc carbonate in a solid state into a polymer solution, adding a physiologically active substance (hormone, etc.), and dispersing the physiologically active substance and a metal cation component separately into a biodegradable polymer.
Although, as described above, various attempts have been made to produce a sustained-release preparation while retaining the physiological activity of a physiologically active polypeptide, a clinically satisfactory preparation has not been obtained yet since some physiologically active polypeptides have problems such as a low entrapment ratio of the physiologically active polypeptide in the preparation, an excess release at an initial stage after administration, an unattained constant release over a long period of time, or an unretained satisfactory blood concentration over a long period of time. Further, production methods, in many cases, are not suitable for industrialization which premises a large-scale production in the present situation.
In a method for producing a sustained-release preparation by using what is called a S/O emulsion which is obtained by adding and dispersing the physiologically active polypeptide powder (solid phase: hereafter sometimes referred as an S phase) discretely into an organic solvent in which is dissolved a polymer (O phase), it is possible to entrap the physiologically active polypeptide in relatively stable manner. However, it is necessary that a large quantity of the physiologically active polypeptide is efficiently handled as a solid. Furthermore, there are many problems in the process for producing the sustained release preparation, such as controlling of the particle size of the powder in the S/O dispersion which is essential, because the particle size influences greatly the quality of the obtained sustained-release preparation.
Therefore, it is desired to have a method for producing the sustained-release preparation by which it is possible to produce the sustained-release preparation with stable quality in high yield in large scale in addition to satisfying any problem such as maintaining the stability of the physiologically active polypeptide, the preparation of powder which is superior in handling the atomization of the powder in the process for producing the preparation.
DISCLOSURE OF THE INVENTION
The present inventors studied to solve the above problems, and unexpectedly, first discovered the physiologically active polypeptide powder which has a small particle size in addition to which is superior for handling in the process for producing the preparation, while the physiological activity of the, polypeptide is maintained, is achieved where a water-miscible organic solvent and/or a volatile salt is/are added into the aqueous solution of the physiologically active polypeptide, and then the resultant solution is lyophilized. Furthermore, the present inventors found out unexpectedly the fact that the entrapment ratio and the sustained-release effect of the preparation are improved where the physiologically active polypeptide powder obtained as mentioned above is dispersed, into a solution of a biodegradable polymer dissolved into an organic solvent, and then the organic solvent is removed to produce the sustained-release preparation. As mentioned above, the present inventors accomplished the present invention.
The present invention is concerned with
(1) A method for producing a sustained-release preparation, which comprises dispersing a physiologically active polypeptide into an organic solvent solution of a biodegradable polymer and removing the organic solvent: wherein the polypeptide is a powder obtained by lyophilizing an aqueous solution of the polypeptide which solution has a water-miscible organic solvent and/or a volatile salt;
(2) the method according to the above (1), wherein the average particle size of the powder is not more than 10 &mgr;m;
(3) the method according to the above (1), wherein the physiologically active polypeptide is growth hormone;
(4) the method according to the above (3), wherein the growth hormone is human growth hormone:
(5) the method according to the above (1), wherein the water-miscible organic solvent is alcohol;
(6) the method according to the above (5), wherein the alcohol is methanol or ethanol;
(7) the method according to the above (5), wherein the alcohol is ethanol;
(8) the method according to the above (1), wherein the volatile salt is an ammonium salt;
(9) the method according to the above (8), wherein the ammonium salt is ammonium acetate, ammonium bicarbonate or ammonium carbonate;
(10) the method according to the above (8), wherein the ammonium salt is ammonium acetate;
(11) the method according to the above (5), wherein a final concentration of the alcohol to be added to the aqueous solution of the physiologically active polypeptide is 0.03 to 0.5% (V/V);
(12) the method according to the above (8),
Iwasa Susumu
Misaki Masafumi
Yamagata Yutaka
Chao Mark
Fubara Blessing
Page Thurman K.
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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