# US 5,346,696 A · Asialoglycoprotein - conjugated medicinal agent > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,346,696 A - Document ID: US5346696A - Status: Granted - Kind: A - Application number: 07/983,595 - Filed: 1993-02-04 - Granted: 1994-09-13 - Earliest claimed: 1991-06-19 - Assignees: Korea Green Cross Corporation - Inventors: Chung Y. Kim; Hyo S. Lee - Web page: https://patentgrep.com/patent/US5346696A ## CPC - C07K 14/47: from mammals - A61K 47/62: the modifying agent being a protein, peptide or polyamino acid - A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics - A61P 31/12: Antivirals - A61P 35/00: Antineoplastic agents - C07K 14/555: Interferons [IFN] - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract The present invention relates to a conjugated medicinal agent prepared by combining asialoglycoprotein with a medicine which acts specifically on the liver. The conjugated medicinal agent of the present invention has the following formula (1): P-(S)x-Gal-GA-R, wherein in the P-(S)x-moiety, P is a peptide residue of a human serum glycoprotein and S is a sugar residue of a human serum glycoprotein; Gal is galactose residue; GA is glutaraldehyde residue; x is an integer equal to or greater than 1; and R is a medicinal component selected from the group consisting of interferon, acyclovir sodium, ribavirin, vidarabine, zidovudine, suramin, anti-sense oligonucleotide, ribozyme, leucovorin calcium, sodium-meglumine diatrizoate, gadolinium-DTPA, glutathione (GSH), prostaglandins, .sup.99m Tc and .sup.131 I. The present invention also includes a process for preparing the conjugated medicinal agent of formula (I), a pharmaceutical composition containing the conjugated medicine and the use of the conjugated medicine. ## Claims ### Claim 1 The asialoglycoprotein-conjugated medicinal agent having the following formula (1), P-(S)x-Gal-GA-INF (1) wherein P is a peptide residue of a human serum glycoprotein; S is a sugar residue of a human serum glycoprotein Gal is a galactose residue; GA is a glutaraldehyde residue; x is equal to or greater than 1; and INF is interferon. ### Claim 2 (depends on 1) The conjugated medicinal agent of claim 1, wherein INF is alpha interferon. ### Claim 3 (depends on 1) The conjugated medicinal agent of claim 1, wherein INF is beta interferon. ### Claim 4 (depends on 1) The conjugated medicinal agent of claim 1, wherein INF is gamma interferon. ### Claim 5 (depends on 1) The conjugated medicinal agent of claim 1, wherein said P-(S)x-Gal- is a desialylated human serum glycoprotein residue in which P is a protein residue of a human serum glycoprotein, S is a sugar residue of a human serum glycoprotein and Gal is a D-galactose residue. ### Claim 6 (depends on 5) The conjugated medicinal agent of claim 5, wherein said desialylated human serum glycoprotein is selected from the group consisting of asialoorosomucoid, asialofetuin, asialoceruloplasmin, asialohaptoglobin, asialothyroglobulin and asialomacroglobulin. ### Claim 7 (depends on 1) The conjugated interferon of claim 1, wherein INF is recombinant interferon. ### Claim 8 (depends on 1) A pharmaceutical composition for treating hepatitis comprising an amount of a conjugated recombinant interferon of formula (1) of claim 1 in sufficient amount to inhibit the replication of hepatitis virus present in the liver cells of a patient affected with viral hepatitis and a pharmaceutically acceptable carrier, adjuvant or excipient therefor. ### Claim 9 (depends on 8) The pharmaceutical composition of claim 8 suitable for intravenous administration. ### Claim 10 (depends on 1) A method of treating viral hepatitis in a patient suffering from viral hepatitis by administrating an amount of a conjugated interferon of formula (1) of claim 1 sufficient to inhibit the replication of hepatitis virus present in the liver cells of said patient affected with viral hepatitis. ### Claim 11 (depends on 10) The method of claim 10 wherein said conjugated interferon is administered by intravenous administration. ### Claim 12 (depends on 1, 11) The method of claim 11 wherein the amount of a conjugated interferon of formula (1) of claim 1 sufficient to inhibit the replication of hepatitis virus present in the liver cells of said patient affected with viral hepatitis is 0.2 to 2 million international units on the basis of interferon per square meter of body surface, one time for one or two days. ### Claim 13 A process for preparing a conjugated interferon of formula (1) P-(S)x-Gal-GA-INF (1) wherein P is a peptide residue of a human serum glycoprotein; S is a sugar residue of a human serum glycoprotein Gal is a galactose residue; GA is a glutaraldehyde residue; x is equal to or greater than 1; and INF is interferon, comprising: providing a Cohn fraction V supernatant of human serum; treating the Cohn fraction V supernatant of human serum to separate alpha(1)-acid glycoprotein having the formula P-(S)x-Gal-NANA therefrom, wherein NANA is N-acetyl neuraminic acid, and recovering the alpha(1)-acid glycoprotein; treating the recovered alpha(1)-acid glycoprotein with neuraminidase to remove sialic acid and to obtain asialoglycoprotein of formula P-(S)x-Gal; linking the asialoglycoprotein with interferon by means of a glutaraldehyde (GA) crosslinking method; and recovering the conjugated interferon of formula P-(S)x-Gal-GA-INF. ### Claim 14 (depends on 13) The process of claim 13 wherein the Cohn fraction V supernatant of human serum is treated with DEAE-Sephadex or CM-Cellulose chromatography to separate the alpha(1)-acid glycoprotein of formula P-(S)x-Gal-NANA from the Cohn fraction V supernatant. ### Claim 15 (depends on 13) The process of claim 13 wherein the alpha(1)-acid glycoprotein is orosomucoid. ### Claim 16 A process for preparing a conjugated interferon of formula (1) P-(S)x-Gal-GA-INF (1) wherein P is a peptide residue of a human serum glycoprotein; S is a sugar residue of a human serum glycoprotein Gal is a galactose residue; GA is a glutaraldehyde residue; x is equal to or greater than 1; and INF is interferon, comprising; providing human blood serum which includes a human serum glycoprotein of the formula P-(S)x-Gal-NANA, characterized in that the residue adjacent to the sugar residue is D-galactose (Gal) and the last residue is N-acetyl neuraminic acid (NANA); treating the human blood serum to separate the human serum glycoprotein P-(S)x-Gal-NANA from the human blood serum and recovering the human serum glycoprotein P-(S)x-Gal-NANA; treating the recovered human serum glycoprotein (P-(S)x-Gal-NANA with neuraminidase to remove NANA and to obtain asialoglycoprotein (P-(S)x-Gal); linking the asialoglycoprotein, (P-(S)x-Gal), with interferon by means of a glutaraldehyde(GA) crosslinking method; and recovering the conjugated interferon of formula P-(S)x-Gal-GA-INF (1). ### Claim 17 (depends on 16) The process of claim 16 wherein the human blood serum is a Cohn fraction V supernatant of human serum and which is treated with DEAE-Sephadex or CM-Cellulose chromatography to separate the human serum glycoprotein of the formula P(S)x-Gal-NANA from the Cohn fraction V supernatant. ### Claim 18 (depends on 1) A pharmaceutical composition for treating hepatitis comprising a hepatitis-treating effective amount of a medicinal agent of claim 1 and a pharmaceutically acceptable carrier, adjuvant or excipient therefor. ### Claim 19 (depends on 18) A pharmaceutical composition of claim 18 suitable for intravenous administration.