MXPA94003076A - Liesferas that understand gonadotrop - Google Patents
Liesferas that understand gonadotropInfo
- Publication number
- MXPA94003076A MXPA94003076A MXPA/A/1994/003076A MX9403076A MXPA94003076A MX PA94003076 A MXPA94003076 A MX PA94003076A MX 9403076 A MX9403076 A MX 9403076A MX PA94003076 A MXPA94003076 A MX PA94003076A
- Authority
- MX
- Mexico
- Prior art keywords
- gonadotropin
- dried
- fsh
- lyosphere
- lyospheres
- Prior art date
Links
- 102000006771 Gonadotropins Human genes 0.000 claims abstract description 17
- 108010086677 Gonadotropins Proteins 0.000 claims abstract description 17
- 239000002622 gonadotropin Substances 0.000 claims abstract description 17
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 238000007710 freezing Methods 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 10
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 10
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 10
- 239000001509 sodium citrate Substances 0.000 description 10
- 239000005720 sucrose Substances 0.000 description 10
- 239000011778 trisodium citrate Substances 0.000 description 10
- 229920001213 Polysorbate 20 Polymers 0.000 description 7
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 7
- 229940068977 Polysorbate 20 Drugs 0.000 description 5
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 5
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 4
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229940028334 Follicle Stimulating Hormone Drugs 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940094892 Gonadotropins Drugs 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000002485 urinary Effects 0.000 description 2
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 229940075554 Sorbate Drugs 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- -1 poly vmylpyrrolidone Chemical compound 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to lyospheres comprising gonadotropin, its preparation, as well as to pharmaceutical preparations containing them.
Description
"LIOSFER S THAT UNDERSTAND GONADOTROPHINE"
INVENTORS: ARNOLD TITUS PHILIP SKRABANJA and HERMÁN VROMANS, Dutch citizens, residing at eßzßnhof 6209, 6536 AN Nijmßgen, The Netherlands; and Vßrwßrstraat 11, 5343 PB Oss, The Netherlands.
CAUSAHABIENTE: AKZO NOBEL N. V., a Dutch company, with address at Vßlpßrwßg 76, 6824 BM Arnhßm, The Netherlands.
RggUMEN
The invention relates to lyospheres comprising jonadotropin, to its preparation, as well as to pharmaceutical preparations containing them.
DESCRIPTIVE MEMORY
The invention relates to lyospheres comprising gonadotropin, its preparation, as well as pharmaceutical preparation comprising them. Liospheres are drops dried by freezing. they know the freeze-dried particles as Price's spherical and coinventores (US 3,655,838). These spherical granules comprise material for immunological reactions. The lyospheres comprising biologically active materials are known, for example, from USP 3,932,943, and also from many other patents. The known advantages of liosfer are the uniformity of the particles, the ease of handling the products, the faster freeze drying process, less degradation of the freeze drying process and the improved dissolution properties. Surprisingly, it has now been found that lipospheres comprising gonadotropin have an improved storage life compared to conventionally freeze-dried gonadotropi. In addition, with additional advantages it has been found that the recovery of gonadotropin, after freeze drying of the lyospheres, is better than the recovery after conventional freezing or p freezing, and that the analysis properties are improved.
Therefore, the invention relates to a liosphere comprising a ganadotropirici. Preferably, said gonadotropm is HCG (human gonadotropin), FSH (follicle stimulating hormone) or LH (leutinizing hormone), or a combination thereof. Said gonadotropins can be obtained by isolation from natural sources or by recombinant techniques. Most preferably, said gonadotropin is rec-FSH. The spheres may also comprise pharmaceutically acceptable auxiliaries such as fillers, stabilizers and surfactants. Customary auxiliaries are, for example, sucrose, mannose, dextran, Tween, poly vmylpyrrolidone, sodium citrate and the like. The beads can be prepared by freezing droplets of an aqueous gonadotropy solution which, optionally, also comprises the auxiliaries. To obtain the drops of the required size, the solution can be sprayed in a cold bath (for example, as described in DT 2,140,747, EP 81913, or US 3,928,566), to liquid nitrogen (for example, as described in J5 9169, 504), or towards a refrigerated drum (e.g., as described in USP 3892876), or a chilled plate (e.g., as described in US 4,501,719). Various other methods in the art are well known. The lyospheres of the invention may be processed to a pharmaceutical preparation. The term "pharmaceutical preparation" means an ampoule or syringe or any other means in which the lyospheres can be introduced, and in such a way, can be used by physicians. When the lyospheres comprise FSH or rec-FSH as the gonadotropin, the pharmaceutical preparations comprise 75, 100, 150, 300 and, preferably, 50 international units of FSH. Preferably, each lyosphere comprises a fixed amount of gonadotropin, for example, 50 international units. The determination of the quantity of the international units present in the pharmaceutical preparation can simply be achieved by counting the number of lyospheres. When the liosphere contains hCG or rec-CG as the gonadotropin, the pharmaceutical preparations preferably comprise 1, 2.5, 5, 10 or 5000 IU of the gonadotropin. The lyospheres of the invention can be used for medical applications, when gonadotropins are required. Liospheres containing FSH or rec-FSH are particularly useful for application in IVF (in vitro fertilization). The invention is further illustrated by the following examples.
EXAMPLE 1
Liospheres were prepared in the following manner. The ingredients (gonadotropin and the excipients sucrose, sodium citrate and polysorbate 20) were dissolved in water and diluted to the desired final concentration. The pH was adjusted to 7 using hydrochloric acid and / or sodium hydroxide. After filtration through a disposable 0.2 μm Durapore membrane filter, 100 μl droplets were formed and frozen, for example, in liquid nitrogen. The frozen drops were collected and dried by freezing at -50 ° C, in a manner known per se. Freeze dried droplets (lyospheres) were transferred to a vial or ampoule.
EXAMPLE 2
The recovery of freeze-dried lyospheres and conventional freeze-dried lyospheres was compared by means of EIA (enzyme immunological analysis), using aqueous formulations containing 10 U of rec-HCG.
RESULT
content of HCG in U, after formulation dried by congel ation l ips. fgr.as? q ?? E > p? ippal
A 10 7. 4 B __i 7.2 Formulations per ml: A: 50 mg of sucrose, 0.04 mg of Tween 20, 0.92 mg of sodium citrate, 10 U of rec-HCG. B: 50 mg of sucrose, 0.20 mg of Tween 20, 0.92 mg of sodium citrate, 10 U of rec- HCG.
AXIS 5
A 500 μl solution containing 75 IU of rec-FSH, 5 mg of sucrose, 7.35 mg of sodium citrate and 0.1 mg of palisorbate 20, was freeze-dried conventionally and compared to a 100 μl solution containing 75 LJI of rec-FSH, 25 mg of sucrose, 7.35 mg of sodium citrate and 0.02 mg of pol sorbate 20, which had been freeze-dried with 1 os fera. Both products dried by freezing were stored for six months at 4, 25, 30, 40 and 50CC and for 12 months at 4, 25 and 30 ° C. After six and 12 months, the activity was determined in vitro according to the method of lannatirts et al. In Roland et al. (Ed.): Neuro-endocrinology of reproduction, 1987, pages 49-58, and expressed as a percentage of the activity of the mixture stored at 4"C.
Tempera- The conventional sphere in ° C activity in percent é 1 < __ 12 months
4 100 100 100 100 25 - 96 102 73 30 118 85 97 77 40 118 76 - 50 __} - fifty _.
A 500 μl solution containing 5 IU of rec-HCG, 25 mg of sucrose, 0.46 mg of sodium citrate and 0.1 mg of polysorbate 20 was conventionally dried by freezing and compared with a 100 μl solution containing 5 IU. of HCG, 25 mg of sucrose, 0.46 mg of sodium citrate and 0.02 mg of polysorbate 20, which was freeze-dried as a lyosphere. Both dried products were stored by freezing for 2 months at -18 and 50 ° C. After two months, the activity was determined by EIA and expressed as a percentage of the activity of the sample stored at -18 ° C.
Conventional lyosphere temperature in ° C activida gn Pr? EntaJe -18 100 100 50 §4. 59
EXAMPLE 5
A 500 μl solution containing 5 IU of urinary HCG, 20 mg of sucrose, 0.46 mg of sodium citrate and 0.1 mg of polysorbate 20 was conventionally dried by freezing and compared to a 100 μl solution containing 5 IU of Urinary HCG, 25 mg of sucrose, 0.46 mg of sodium citrate and 0.02 mg of polysorbate 20, which had been freeze-dried as a lyosphere. Both were stored
Claims (7)
1. - A liosphere, characterized in that the liosphere comprises a gonadotropin.
2. The lyosphere according to claim 1, further characterized in that the gonadotropin is HCG, FSH or LH or a combination thereof.
3. The lyosphere according to claim 1 or 2, further characterized in that the gonadotropin is mixed with pharmaceutically acceptable auxiliaries.
4. - The lyosphere according to any of claims 1 to 3, characterized in that it is used in IVF.
5. The preparation of the lyosphere according to any of claims 1 to 3, further characterized in that the gonadotropin is freeze-dried as a drop.
6. A pharmaceutical preparation, characterized in that it comprises the lyospheres of any of claims 1 to 3.
7. The pharmaceutical preparation according to claim 6, further characterized in that the lyospheres comprise 50 IU of FSH or rec-FSH. In testimony of which, I sign the above in this City of Mexico, D. F., on the 27th day of the month of April 1994. BY AKZO NOBEL N. V. APPOINED Ing. Javier Saucedo C,
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB93201215.6 | 1993-04-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA94003076A true MXPA94003076A (en) | 2000-07-01 |
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