IE903479A1 - Stabilized Leukocyte-Interferons - Google Patents
Stabilized Leukocyte-InterferonsInfo
- Publication number
- IE903479A1 IE903479A1 IE347990A IE347990A IE903479A1 IE 903479 A1 IE903479 A1 IE 903479A1 IE 347990 A IE347990 A IE 347990A IE 347990 A IE347990 A IE 347990A IE 903479 A1 IE903479 A1 IE 903479A1
- Authority
- IE
- Ireland
- Prior art keywords
- composition according
- ifn
- vol
- interferon
- acid
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Abstract
Human interferon is stabilised with disaccharides and, where appropriate, bile acid or bile acid derivatives.
Description
The present invention is concerned with the stabilization of leucocyte interferon (IFN-a), especially in the form of lyophilizates, using disaccharides and optionally bile acids or bile acid derivatives .
Under IFN-α there is to be understood a body-specific protein having antiviral and immunoregulatory activity. The antiviral effect is achieved not by a direct influence on the viruses themselves, but by an activity on their target cells in the sense of a protection against the viral infection. In addition to the antiviral activity, α-interferon can exert objectifiable effects on cancer tumors, which makes it suitable for use in cancer therapy, and it influences the immune system of the body in that e.g. it activates macrophages and NK cells and increases the expression of various immunologically significant constituents of the cell membrane.
Thanks to recombinant DNA technology, IFN-α can today be prepared in a microbiological manner in amounts which hitherto could not be made available by isolation from natural material (leucocytes, lymphocytes) and purification in spite of the greatest efforts.
This new technology has opened for the first time a way for the intensive clinical testing and possible wide
3Q therapeutic use of IFN-α and has made possible an adequate supply of the active substance for persons seeking a treatment with the active substance.
Ar/5.7.90
- 2 It has now emerged that IFN-α in pure form is not completely stable and suffers loss of its biological activity during storage.
Different adjuvants have therefore already been used for the stabilization of IFN-α. A certain stabilization of IFN-α has been achieved by the addition of glycine (see e.g. publ. PCT Application 86/00531 and European Patent. Publ. No. 82 481). whereby, however, albumin is
1Q preferably simultaneously added.
In efforts to achieve a good stabilization of IFN-a over the longest possible period while avoiding the use of high-molecular compounds such as serum albumin, gelatine, 15 dextran or starch derivatives, it has been found that this is successful using disaccharides and optionally bile acids or bile acid derivatives.
The present invention is accordingly concerned with
2q compositions, especially in the form of lyophilizates, which contain a disacchacide and optionally bile acids or bile acid derivatives, as well as a process for their manufacture which comprises treating an IFN-α solution with a disaccharide and optionally bile acids or bile acid derivatives and. if desired, lyophilizing the solution obtained. The present invention is also concerned with pharmaceutical preparations based on the compositions in accordance with the invention as well as the use of disaccharides and optionally bile acids or bile acid derivatives for the stabilization of IFN-a.
The compositions in accordance with the invention can be used for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of a large number of infections and immunoregulatory anomalies, especially neoplasms.
- 3 The stabilization can be applied to natural or recombinant IFN-α (r-IFN-a). Recombinant IFN-aA (r-IFN-aA) is an especially preferred IFN-α in connection with the present invention. The content of 5 TFN-α in the compositions in accordance with the invention is not critical. The concentration range extends over more than the power of ten and is limited at the upper end essentially only by the solubility of IFN-a.
Tn the case of human IFN-α there come into consideration, for example, concentrations up to 5*10 international units (I.U.)/ml, with a preferred range 6 8 being 0.1 x 10 to 1 x 10 I.U./ml. especially 1 χ 106 to 5 χ 107 I.U./ml.
The disaccharide, preferably lactose or saccharose, is added to the IFN-α solution in a concentration of 0.5% to 15% (wt./vol.), preferably 5% (wt./vol.).
The bile acids or the bile acid derivatives can be
2q e.g. cholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxyoholic acid, taurochenodeoxycholic acid, glycocholic acid or taurocholic acid, with glycocholic acid being especially preferred. It is added to the
IFN-α solution in a concentration of 0.01 to 3% (wt./vol.), preferably 0.5% (wt./vol.).
Further adjuvants for the pH-adjustment, e.g. NaOH, pH-buffering, e.g. phosphate buffer and citrate buffer.
isotonization, e.g. sodium chloride, and preservation of the preparation, e.g. methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, as well as for strengthening the structure of the lyophilizate, e.g. glycine, can also be added .
Particulars of the invention are described in the following Examples.
The r-IFN-αΑ used in the Examples can be obtained in pure form according to known procedures described in the literature or according to procedures obvious to a person skilled in the art.
In order to determine the antiviral activity of the r-IFN-aA. there was used a cytopathological test with MDBK (Madison Darby Bovine Kidney) cells and VSV (vesicular stomatitis virus) viruses, which has been described by Rubinstein et al. [J. Virol. 37. 755-758 (1981)]. MDBK cells and VSV viruses are generally accessible and can be obtained e.g. from the American Type Culture Collection (ATCC) (MDBK: ATCC Nos. CCL 21 and CRL 6071; VSV: ATCC No. VR-1 59).
For the stability testing, solutions with r-IFN-aA and the additives under investigation were lyophilized and stored at different temperatures (5°, 25°. 35°. 45°. 55° and 65°C). After fixed time intervals the antiviral activity of the IFN-αΑ still present in the lyophilizates was determined.
The following Examples illustrate the invention without limiting it.
Example 1 mio. I.U. of r-IFN-αΑ were taken up in l ml of water containing human serum albumin, glycine or lactose and optionally further adjuvants (see Table 1). The solutions obtained were sterile-filtered (membrane filter, 0.2 urn pore size) and loaded in 10 ml glass vials in a steam-sterilized freeze-dryer. After freezing the solutions at -40°C during 4 h the primary drying of the lyophilization process was carried at about -30°C under a pressure of 0.1 mbar during 14 h. Subsequently, the
- 5 secondary drying was carried out under a full vacuum at +20°C during about 4 h. The glass vials were closed with suitable aluminium caps in the freeze-dryer under a N2 atmosphere. They were subsequently subjected to different stability tests, the results of which are compiled in Table 1.
- 6 Table 1
Composition of the lyophilizates containing r-IFN-aA
Lyophilizate from:
r-IFN-αΑ (mio. I.U.) 3.0
Sodium chloride (mg) 9.0
Human serum albumin (mg) 5.0 Mannitol pyrogen-free (mg) Glycine (mg)
Lactose (mg)
NaH2PO4.H2O ad pH 7.4 NaOH IN ad pH 7.4 Water for injection
Antiviral activity ( in mio. I.U.) after manufacture of the lyophilizate weeks/ 5°C /25°C /35°C /45°C /55°C /65°C months/ 5°C /25°C /35°C /45°C months/ 5°C /25°C “ /35°C /45°C
3.0
3.0
3.0
3.0
.0
.0
50.0
.0
q. s. - - q. s.
1.0 ml
1.0 ml
q.s. 1.0 ml
q.s. 1.0 ml
1.0 ml
3.0
3.0 2.7
3.2 3.0
3.2 2.7
3.3 2.8
2.7 2.0
2.8 1.5
2.1 0.6
2.7 2.5 2.5 2.3 2.4 2.1
1.7 1.2
3.5
3.3
2.6 n. t
3.1 3.1 1.9 1.7
3.3
2.3
2.8 3
3.4 3
3.3 2
3.0 2
2.4 2.
1.8
1.5
1.2
0.9
0.8
0.4
3.0 3.6 3.1 3.2 3.1 2.7 2.8 1.3
3.2 3.1 3.2 2.4 3.0 2.4 3.0 1.1
12 months/ 5°C 3.7 n.t. 3.0 2.8 II /25°C 2.9 n.t. 2.9 2.5 5 II /35°C 2.1 n.t. 2.7 1.3 II /45°C n.t. n.t. 2.7 1.6
n.t. = not tested q.s. = quantum satis
- 8 The best results were achieved with the lactose-containing lyophilizate (see column 3). This preparation exhibited an outstanding stability even after long-term storage at the storage temperature of 45°C. which is almost prohibitive for IFN-α. This result could also be confirmed unequivocally in experiments with lyophilizates containing 1 mio. I.U. of r-IFN-αΑ (see Table 2).
- 9 Table 2
Composition of the lyophilizates containing r-IFN-aA
Lyophilization from:
r-IFN-αΑ (mio. I.U.) 0.5 0.5 Glycine (mg) 10.0 - Lactose (mg) - 50.0 NaOH IN ad pH 7.4 q. s . q.S Water for injection 1.0 ml 1.0 Antiviral activity
(in mio. I.U.) after manufacture of the
lyophi 1izate 0.4 0.4 2 weeks/ 5°C 0.5 0.4 II /25®C 0.4 0.4 II /35°C 0.4 0.4 II /45°C 0.3 0.3 II /65°C 0.2 0.3 3 months/ 5°C 0.5 0.5 II /25°C 0.4 0.4 II /35°C 0.3 0.4 II /45°C 0.2 0.4 6 months/ 5°C 0.4 0.5 II /25°C 0.4 0.4 II /35°C 0.2 0.4 II /45°C 0.05 0.3
- 10 Example 2
The stability of lyophilizates containing r-IFN-aA and saccharose was investigated in an analogous manner to Example 1. It was established that the stabilization of r-IFN-αΑ obtained with lactose can also be achieved with saccharose (see Table 3).
- 11 Table 3
Composition of the lyophilizates containing r-IFN-aA
Lyophilizate from: 1 2 3. r-IFN-αΑ (mio. I.U.) 3 3 3 Sodium chloride (mg) 9.0 - - Human serum albumin 5.0 - - Glycine - 20.0 10.0 Saccharose (mg) - - 50.0 NaH2PO4 H2O ad pH 7.4 - q.s. - NaOH IN ad pH 7.4 - - q.s Water for injection ad 1.0 ml 1.0 ml 1.0 Antiviral activity
ml (in mio. I.U.) after manufacture of the
lyophilizate 2.7 3.0 3.4 3 months/ 5°C 2.7 2.5 3.9 “ /25’C 2.5 2.3 3.6 ·' /35°C 2.4 2.1 3.7 /45°C 1.7 1.2 - 6 months/ 5°C 3.5 3.1 4.0 /25°C 3.3 3.1 3.7 /35°C 2.6 1.9 3.7 • /45°C — 1.7 -
- 12 Example 3
The stability of lyophilizates containing r-IFN-aA in high concentrations and lactose or saccharose was investigated in an analogous manner to Example 1. It was established that the stabilization of IFN-α produced using disaccharides can also be achieved in the case of high rIFN-αΑ concentrations (see Table 4).
- 13 Table 4
Composition of lyophilizates containing r-IFN-αΑ
Lyophilized from: 1 2 3 4 r-IFN-αΑ (mio. I.U.) 9.0 9.0 18.0 18.0 Lactose 50.0 mg - 50.0 mg - Saccharose - 50.0 mg - 50.0 mg Glycine 10.0 mg 10.0 mg 10.0 mg 10.0 mg NaOH IN ad pH 7.4 - - - q.s. Water for injection ad 1.0 ml 1.0 ml 1.0 ml 1.0 ml Antiviral activity
(in mio. I.U.) after manufacture of the
lyophi1izate 8.8 8.9 18.3 19.9 3 months/ 5eC 9.9 9.6 17.8 23.4 /25°C 10.0 10.5 19.1 23.2 /35°C 10.3 10.1 20.5 n. t. /45°C 10.4 10.9 22.0 n. t. 6 months/ 5°C 9.7 n. t. 17.8 19.1 /25°C 9.9 n. t. 21.1 21.9 '· /35°C 8.9 n. t. 16.6 n. t. /45°C 8.4 n. t. 16.1 n. t.
- 14 Example 4
The stability of lyophilizates containing r-IFN-aA, lactose and glycocholic acid was investigated in an analogous manner to Example 1. The results obtained are compiled in Table 5.
- 15 Table 5
Composition of the lyophilizates containing r-IFN-aA lyophilizate from:
r-IFN-αΑ (mio. I.U.) 1 3 9 18
Glycocholic acid (mg) 5.0 5.0 5.0 5.0 Lactose (mg) 50.0 50.0 50.0 50.0 Sodium chloride (mg) 2.5 2.5 2.5 2.5 NaOH IN ad pH 7.4 q.s. q.s. q.s. q.s Water for injection ad 1.0 ml 1.0 ml 1.0 ml 1.0
Antiviral activity (in mio. I.U.) after manufacture of the
lyophilizate 0.96 2.97 8.56 18.8 14 days/ 5°C 0.85 - - - / RT 0.92 - - - /35°C 0.85 - - - 25 /4 5 °C 0.83 - - - 6 months/ 5°C 1.02 2.89 9.2 18.7 / RT 1.1 2.82 8.7 18.7 /35°C 1.06 3.11 8.9 18.3 30 /45°C 0.99 2.71 8.94 n. t
Claims (15)
1. A composition containing a-interferon, a disaccharide and optionally bile acids or bile acid g derivatives. 7. A composition according to claim l, wherein the α-interferon is a natural or a recombinant human leucocyte interferon. 3. A composition according to claim 2. which contains r-IFN-aA. 4. A composition according to any one of claims 1 to 3 in the form of a lyophilizate, i b 5. A composition according to any one of claims 1 to 4, wherein the disaccharide is lactose or saccharose.
2. Q 6. A composition according to any one of claims 1 to
3. 5, which cotitains 0.5% to 15% (wt./vol.) of lactose or saccharose. 7. A composition according to any one of claims 1 to 25 5. which contains 5% (wt./vol.) of lactose or saccharose. 8. A composition according to any one of claims 1 to
4. 6, which contains 0.01% to 3.0% (wt./vol.) of bile acids or bile acid derivatives, preferably 0.1% to 1.0% (wt. 30 vol.) of glycocholic acid.
5. 9. A composition according to any one of claims 1 to 6, which contains 0.5% (wt./vol.) of bile acid derivatives, preferably 0.5% (wt./vol.) of glycocholic 35 acid. - 17
6. 10. (wt./vol acid . A composition containing r-IFN-αΑ, 5% ) of lactose and 0.5% (wt./vol.) of glycocholic
7. 11. A composition according to any one of claims 1-10 as a pharmaceutically active material.
8. 12. A composition according to any one of claims 1-10 as an antivirally and immunoregulatory active material.
9. 13. A process for the manufacture of a composition according to any one of claims 1 to 10. which process comprises treating α-interferon with a disaccharide and optionally bile acids or bile acid derivatives, preferably 15 glycocholic acid, and, if desired, lyophilizing the solution obtained.
10. 14. Pharmaceutical preparations based on a composition according to any one of claims 1 to 10. - 18
11. 15. The use of disaccharides and optionally bile acids or bile acid derivatives, preferably glycocholic acid, for the stabilization of α-interferon. 5
12. 16. The use of a composition according to any one of claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of illnesses.
13. 17. The use of a composition according to any one of 10 claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of viral infections .
14. 18. The use of a composition according to any one of claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of immunoregulaLory anomalies.
15. 19. The use of a composition according to any one of 2q claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of neoplasms. - 19 20. A composition containing a-interferon. a disaccharide and optionally bile acids or bile acid derivatives prepared according to a process as claimed in claim 13. - 20 21. The invention substantially as hereinbefore described, especially with reference to the examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH351489 | 1989-09-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE903479A1 true IE903479A1 (en) | 1991-04-10 |
Family
ID=4257630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE347990A IE903479A1 (en) | 1989-09-28 | 1990-09-27 | Stabilized Leukocyte-Interferons |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0420049B1 (en) |
| JP (1) | JPH03130232A (en) |
| KR (1) | KR910005886A (en) |
| CN (1) | CN1050503A (en) |
| AR (1) | AR244551A1 (en) |
| AT (1) | ATE92334T1 (en) |
| AU (1) | AU636653B2 (en) |
| CA (1) | CA2024046A1 (en) |
| CZ (1) | CZ277712B6 (en) |
| DD (1) | DD298054A5 (en) |
| DE (1) | DE59002183D1 (en) |
| FI (1) | FI904756A0 (en) |
| HU (1) | HU205555B (en) |
| IE (1) | IE903479A1 (en) |
| IL (1) | IL95769A0 (en) |
| IS (1) | IS3631A7 (en) |
| MC (1) | MC2149A1 (en) |
| MX (1) | MX22522A (en) |
| MY (1) | MY106615A (en) |
| NO (1) | NO904218L (en) |
| NZ (1) | NZ235153A (en) |
| PH (1) | PH27531A (en) |
| PT (1) | PT95454A (en) |
| RU (1) | RU2008017C1 (en) |
| YU (1) | YU184090A (en) |
| ZA (1) | ZA907579B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6794194A (en) * | 1993-05-18 | 1994-12-20 | Bukh Meditec A/S | A method for the preparation of interferons |
| AP1168A (en) * | 1996-05-09 | 2003-06-30 | Feronpatent Ltd | Stabilization of interferons in aqueous solution for manufacture of sublingually administered tablets. |
| JP2001526662A (en) * | 1997-05-09 | 2001-12-18 | フェロンパテント リミテッド | Stabilization of interferon in aqueous solution for the production of sublingual tablets |
| CN1191863C (en) * | 1998-03-26 | 2005-03-09 | 先灵公司 | Formulations for protection of PEG-interferon alpha conjugates |
| US6180096B1 (en) | 1998-03-26 | 2001-01-30 | Schering Corporation | Formulations for protection of peg-interferon alpha conjugates |
| CN1175901C (en) * | 1999-12-06 | 2004-11-17 | 天津华立达生物工程有限公司 | Stable water solution of interferon |
| CN101039660B (en) | 2004-08-12 | 2010-10-06 | 先灵公司 | Stable pegylated interferon formulation |
| DE102004048379A1 (en) | 2004-10-01 | 2006-04-13 | "Stiftung Caesar" (Center Of Advanced European Studies And Research) | Spring element made of sputtered shape memory alloy |
| CU23432B6 (en) * | 2005-11-02 | 2009-10-16 | Ct Ingenieria Genetica Biotech | STABILIZED FORMULATIONS CONTAINING GAMMA AND ALFA INTERFERONS IN POTENTIAL PROPORTIONS |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5821691A (en) * | 1981-07-29 | 1983-02-08 | Mochida Pharmaceut Co Ltd | Purifying method of interferon |
| EP0080879B1 (en) * | 1981-11-28 | 1986-10-01 | Sunstar Kabushiki Kaisha | Pharmaceutical composition containing interferon in stable state |
| DE3467706D1 (en) * | 1983-04-28 | 1988-01-07 | Armour Pharma | Pharmaceutical preparation containing purified fibronectin |
| DE3484374D1 (en) * | 1983-08-04 | 1991-05-08 | Green Cross Corp | GAMMA INTERFERON COMPOSITION. |
| IL78231A (en) * | 1985-03-25 | 1990-07-26 | Schering Corp | Stable gamma-interferon formulation |
| US4816568A (en) * | 1986-05-16 | 1989-03-28 | International Minerals & Chemical Corp. | Stabilization of growth hormones |
-
1990
- 1990-08-27 CA CA002024046A patent/CA2024046A1/en not_active Abandoned
- 1990-09-03 NZ NZ235153A patent/NZ235153A/en unknown
- 1990-09-06 CZ CS904328A patent/CZ277712B6/en unknown
- 1990-09-20 EP EP90118132A patent/EP0420049B1/en not_active Expired - Lifetime
- 1990-09-20 AT AT90118132T patent/ATE92334T1/en not_active IP Right Cessation
- 1990-09-20 DE DE9090118132T patent/DE59002183D1/en not_active Expired - Fee Related
- 1990-09-21 AU AU63098/90A patent/AU636653B2/en not_active Expired - Fee Related
- 1990-09-21 ZA ZA907579A patent/ZA907579B/en unknown
- 1990-09-24 HU HU906021A patent/HU205555B/en not_active IP Right Cessation
- 1990-09-24 MC MC902149A patent/MC2149A1/en unknown
- 1990-09-24 MX MX2252290A patent/MX22522A/en unknown
- 1990-09-25 IL IL95769A patent/IL95769A0/en unknown
- 1990-09-26 DD DD90344228A patent/DD298054A5/en not_active IP Right Cessation
- 1990-09-26 MY MYPI90001656A patent/MY106615A/en unknown
- 1990-09-26 PH PH41267A patent/PH27531A/en unknown
- 1990-09-26 AR AR90317958A patent/AR244551A1/en active
- 1990-09-27 JP JP2258806A patent/JPH03130232A/en active Pending
- 1990-09-27 RU SU904831274A patent/RU2008017C1/en active
- 1990-09-27 KR KR1019900015368A patent/KR910005886A/en not_active Application Discontinuation
- 1990-09-27 IS IS3631A patent/IS3631A7/en unknown
- 1990-09-27 NO NO90904218A patent/NO904218L/en unknown
- 1990-09-27 FI FI904756A patent/FI904756A0/en not_active IP Right Cessation
- 1990-09-27 IE IE347990A patent/IE903479A1/en unknown
- 1990-09-27 PT PT95454A patent/PT95454A/en not_active Application Discontinuation
- 1990-09-27 CN CN90108133A patent/CN1050503A/en active Pending
- 1990-09-28 YU YU184090A patent/YU184090A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1050503A (en) | 1991-04-10 |
| CZ277712B6 (en) | 1993-03-17 |
| AU636653B2 (en) | 1993-05-06 |
| MC2149A1 (en) | 1992-03-10 |
| HUT56284A (en) | 1991-08-28 |
| MY106615A (en) | 1995-06-30 |
| KR910005886A (en) | 1991-04-27 |
| HU906021D0 (en) | 1991-03-28 |
| NZ235153A (en) | 1993-03-26 |
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| DE59002183D1 (en) | 1993-09-09 |
| PT95454A (en) | 1991-05-22 |
| IS3631A7 (en) | 1991-03-29 |
| NO904218D0 (en) | 1990-09-27 |
| CA2024046A1 (en) | 1991-03-29 |
| HU205555B (en) | 1992-05-28 |
| AU6309890A (en) | 1991-04-11 |
| MX22522A (en) | 1993-10-01 |
| RU2008017C1 (en) | 1994-02-28 |
| PH27531A (en) | 1993-08-18 |
| AR244551A1 (en) | 1993-11-30 |
| FI904756A0 (en) | 1990-09-27 |
| YU184090A (en) | 1992-09-07 |
| DD298054A5 (en) | 1992-02-06 |
| CS432890A3 (en) | 1992-12-16 |
| NO904218L (en) | 1991-04-02 |
| JPH03130232A (en) | 1991-06-04 |
| ATE92334T1 (en) | 1993-08-15 |
| IL95769A0 (en) | 1991-06-30 |
| EP0420049A1 (en) | 1991-04-03 |
| EP0420049B1 (en) | 1993-08-04 |
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