Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Skin burn or open wound treatment
Reexamination Certificate
2000-09-06
2002-12-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Skin burn or open wound treatment
C424S078020, C424S078030, C424S484000, C424S486000, C424S400000, C514S772000, C514S772100, C514S772300
Reexamination Certificate
active
06491904
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a topical composition containing human epidermal growth factor (hereinafter referred to as “hEGF”). More specifically, the present invention relates to a topical composition which comprises a polyoxyethylene-polyoxypropylene copolymer (Generic name: Poloxamer) having a viscosity of 4-10 cps at 37° C., 60 rpm as the base for topical formulation of naturally occurring HEGF or recombinant human epidermal growth factor (rhEGF). The topical composition of the present invention is useful for the treatment of cutaneous injuries including wounds, incisions, burns, etc.
BACKGROUND ART
hEGF is a polypeptide which consists of 53 amino acid residues with three disulfide bonds [see, Cohen, S. J. Biol. Chem., 237, 1555-1562, 1962; Savage, C. R., J. Biol. Chem. 248, 7669-7672, 1973]. It has been reported that HEGF plays a very important role in controlling the growth of epidermal and cutaneous cells in mammal [see, Sporn, M. B. et al., Nature (London) 313, 745-747, 1985; Sporn M. B. et al., N. Engl. J. Med. 303, 878-880, 1980]. It is also invloved in the process of wound healing [see, Buckley, A. et al., Proc. Natl. Acad. Sci. USA., 82, 7340-7344, 1985] at a molecular level. Since then numerous studies related to the recovery of cutaneous wounds with HEGF have been conducted.
Although HEGF shows a good activity for stimulating the differentiation of epidermal cells in vitro, the development of formulations containing HEGF for the treatment of topical wound is very difficult due to disadvantage in that hEGF exhibits only a little effect in treating wounds when it is clinically applied to wounds. The reasons why hEGF does not show the desired sufficient effect in treating wounds in the living body are that HEGF as the protein is very unstable, particularly in the presence of water, at room temperature, and has less than one hour in half-life which is far shorter than the lag time required for the induction of DNA synthesis of cells in wound site, which is about 8-12 hour [see, J. Surg. Res., 43, 333, 1987]. Furthermore, when HEGF is applied to the skin, HEGF loses its biological activity due to the denaturation and decomposition of HEGF by proteolytic enzymes present in wound site.
In order to provide the desired wound healing effect of hEGF, it is required to continuously maintain the effective level of HEGF by applying hEGF to wound site at any time during initial few days which are most important for wound healing [see, J. Surg. Res., 43, 333, 1987, J. Lab. Clin. Med., 108, 103, 1986]. In this regard, studies to develop the sustained releasing formulation which can continuously deliver HEGF to wound site have been conducted.
As one of the results of such studies, US Patent Specification No. 4,944,948 discloses the hEGF/liposome gel formulation using neutral phospho- lipids, negative-charged phospholipids and cholesterol, which can continuously deliver HEGF to wound site; and EP Publication No. EP 0312208 discloses the aqueous formulation which comprises pharmaceutically acceptable various water- soluble or water-swellable polymers as the base to consistently release hEGF.
However, although the above-mentioned prior art publications disclose the formulations which can continuously release HEGF for 12 hours or more, they are unsuitable for utilizing in industry since they have disadvantage of a little wound healing effect in wound site.
Particularly, in EP Publication No. 0312208, by preparing the gel formulation using polymers, as the base for continuously releasing hEGF for 12 hours or more, at a high concentration, hEGF is slowly released from the gel and continuously delivered to the wound site, and further the gel formulation itself can provide the wound healing effect by forming the coat at the wound site to create the suitable moisture condition at wound site and to prevent the invasion of pathogenic organisms into wound site. However, since this gel formulation has a very high viscosity of 1,000-12,000,000 cps at room temperature, when it is applied to the wound site with rubbing, such rubbing may cause irritation at the wound site. It is very difficult to apply the formulation to the wound having large lesional area and suffering from severe pain, such as bum. Further, the gel formulation forms an excessive coat at wound site to physically inhibit the migration of epidermal cells by mitogenic activity of hEGF thereby retarding effect of hEGF on the wound healing. Therefore, the gel formulation of said prior art publication suffers from serious disadvantage that when it is clinically applied to the wound site, the wound healing effect of hEGF cannot be sufficiently provided.
As mentioned above, since the prior art topical formulations of hEGF do not exhibit the desired sufficient wound healing effect at the wound site, it is very desirable to develop the topical preparation which can sufficiently exhibit the wound healing effect of hEGF in the living body.
Thus, the present inventors have conducted numerous studies to develop the topical preparation which can exhibit a sufficient wound healing effect in the living body. As a result, we have identified that the topical preparation of hEGF using a polyoxyethylene-polyoxy-propylene copolymer having viscosity of 4-10 cps at 37° C., 60 rpm can exhibit the desired good wound healing effect of hEGF, and thus completed the present invention.
DISCLOSURE OF THE INVENTION
Thus, the present invention relates to a composition containing hEGF for topical use.
More specifically, the present invention relates to a topical composition which comprises hEGF as the active ingredient and a polyoxyethylene-polyoxypropylene copolymer having viscosity of 4-10 cps at 37° C., 60 rpm as the base for topical preparation.
In the present specification, the degree of viscosity was indicated by the dimensions of dynes/sec per cm
2
. This dimension referred to herein, unless otherwise indicated, is in centipose (cps) as measured using a Brookfield viscometer. All viscosity values are measured at 37° C., 60 rpm unless otherwise indicated.
BEST MODE FOR CARRYING OUT THE INVENTION
The polyoxyethylene-polyoxypropylene copolymer which is used as the base in the present invention has a viscosity of 4-10 cps, preferably 4-6 cps, at 37° C., 60 rpm. When the viscosity of polyoxyethylene-polyoxypropylene copolymer is less than 4 cps, the physical healing effect which is inherent in polyoxyethylene-polyoxypropylene copolymer is lowered and the releasing rate of hEGF is excessive fast to reduce its wound healing effect. On the other hand, the viscosity of polyoxyethylene-polyoxypropylene copolymer greater than 10 cps is also undesirable since polyoxyethylene-polyoxypropylene copolymer forms an excessive coat on the wound site inhibiting the migration of epithelial cells stimulated by hEGF, thereby lowering the wound healing effect.
In the present invention, by formulating hEGF into a topical preparation for the treatment of wound using polyoxyethylene-polyoxypropylene copolymer having viscosity of 4-10 cps the coat formed from the polymer does not serve as the physical barrier during the wound healing process and exhibits the inherent physical healing effect and further induces a sufficient wound healing effect by hEGF. Therefore, the present topical formulation can exhibit a good wound healing effect when it is applied to the wound site.
The viscosity of polyoxyethylene-polyoxypropylene copolymer is determined depending on temperature and molecular weight and content of polymer. Thus, to obtain the viscosity of polyoxyethylene-polyoxypropylene copolymer of 4-10 cps at 37° C., 60 rpm, it is preferable to use polyoxyethylene-polyoxypropylene copolymer having molecular weight of about 10,000 to 15,000 in the ratio of 5-10 wt % on the basis of a total weight of the composition or to use polyoxyethylene-polyoxypropylene copolymer having molecular weight of about 7,000 to 10,000 in the ratio of 7.5-15 wt % on the basis of a total weight of the composition.
More preferably, it is suitab
Chung Jong Keun
Han Seung Hee
Kang Jin Seok
Lee Byoung Kwang
Lee Seung Yeob
Birch & Stewart Kolasch & Birch, LLP
Daewoong Pharmaceutical Co., Ltd.
Di Nola-Baron Liliana
Page Thurman K.
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