KR20090047474A - Stable lyophilized preparation - Google Patents
Stable lyophilized preparation Download PDFInfo
- Publication number
- KR20090047474A KR20090047474A KR1020097003067A KR20097003067A KR20090047474A KR 20090047474 A KR20090047474 A KR 20090047474A KR 1020097003067 A KR1020097003067 A KR 1020097003067A KR 20097003067 A KR20097003067 A KR 20097003067A KR 20090047474 A KR20090047474 A KR 20090047474A
- Authority
- KR
- South Korea
- Prior art keywords
- freeze
- formula
- compound represented
- formulation
- dried preparation
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 81
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
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- 239000005720 sucrose Substances 0.000 claims abstract description 26
- 235000000346 sugar Nutrition 0.000 claims abstract description 26
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 26
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
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- CZMRCDWAGMRECN-UGDNZRGBSA-N 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 abstract description 25
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- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000006864 oxidative decomposition reaction Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940089985 polyethylene glycol 700 Drugs 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229960000819 sodium nitrite Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HELHAJAZNSDZJO-UHFFFAOYSA-L sodium tartrate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O HELHAJAZNSDZJO-UHFFFAOYSA-L 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 229940046307 sodium thioglycolate Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to (8E, 12E, 14E) -7-((4-cycloheptylpiperazin-1-yl) carbonyl) oxy-3,6,16,21-tetrahydroxy-6,10,12,16 Provided is a lyophilized formulation excellent in stability over time and reconstituted, comprising, 20-pentamethyl-18,19-epoxytricosa 8,12,14-triene-11-oxide. The present invention relates to 1) (8E, 12E, 14E) -7-((4-cycloheptylpiperazin-1-yl) carbonyl) oxy-3,6,16,21-tetrahydroxy-6,10,12 , 16,20-pentamethyl-18,19-epoxytricosa 8,12,14-triene-11-oxide or a pharmacologically acceptable salt thereof, 2) pH adjusting the pH in the formulation to 5-8 A lyophilized formulation containing a modifier and 3) one or more excipients selected from sugars and sugar alcohols is disclosed.
Freeze-dried preparation, anti-tumor action, 12-membered macrolide compound, vial bottle, head space, mannitol, sucrose, lactose
Description
The present invention relates to a stable freeze-dried preparation containing a 12-membered ring macrolide compound having antitumor action.
(8E, 12E, 14E) -7-((4-cycloheptylpiperazin-1-yl) carbonyl) oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20- A 12-membered ring macrolide compound represented by Formula 1, which is pentamethyl-18,19-epoxytricosa-8,12,14-triene-11-oxide, is a compound obtained by chemically modifying a compound found by microbial fermentation. (See, for example, Patent Document 1 below). This compound inhibits angiogenesis by cancer in vitro and inhibits angiogenesis by cancer through inhibition of Vascular Endothelial Growth Factor (VEGF) production in the hypoxic state. It is known to have a function of inhibiting proliferation of solid tumor cells.
In order to develop the compound represented by the formula (1) as an active ingredient as an actual drug, it is necessary to formulate it in various dosage forms. In formulation, it is formulated as a solid, a liquid, or the like depending on the nature of the active ingredient.
Patent Document 1: International Publication WO03 / 099813
<Start of invention>
Problems to be Solved by the Invention
In the present invention, when the formulation of the compound represented by the formula (1) was examined, in the formulation of the preparation for injection, the compound represented by the formula (1) as an active ingredient is not sufficiently stable in solution, and development as an aqueous injection is difficult. It turned out. On the other hand, since the compound represented by the formula (1) has a good stability in the crystalline powder state, it has been formulated as a powder-filled formulation, but since the dissolution rate of the crystal of the compound represented by the formula (1) is slow, it is dissolved and formulated during use. It has also been found that there is a problem such as requiring a long time.
In view of the above circumstances, an object of the present invention is to provide a freeze-dried preparation comprising a compound represented by the formula (1) or a pharmacologically acceptable salt thereof having excellent stability over time and excellent solubility during reconstitution. To provide.
Means for solving the problem
MEANS TO SOLVE THE PROBLEM As a result of earnestly researching in order to solve the said point, it is excellent in time stability by lyophilizing the compound represented by General formula (1) or its pharmacologically acceptable salt together with a specific pH adjuster and a specific excipient, It was found that a lyophilized formulation having excellent solubility in reconstitution was obtained. In particular, in the lyophilized formulation, when an excipient present as an amorphous powder was used, it was found that a lyophilized formulation having a large stabilizing effect was obtained as the lyophilized formulation. Moreover, when citric acid and its salt were used especially as a pH adjuster, it discovered that the stabilizing effect as a lyophilized formulation is large. Furthermore, when glycine, cyclodextrins, and polyethylene glycol were added as a stabilizer of the said formulation, it discovered that further stability improved. In addition, the inventors have found that the combination of an antioxidant and nitrogen substitution of the head space of the vial bottle as a container contribute to stabilization, and have completed the present invention.
That is, the structure shown below discovered that the initial objective of this invention could be achieved, and came to complete this invention. That is, according to the first aspect of the present invention,
1) a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof,
2) a pH adjuster for adjusting the pH in the formulation to 5-8, and
3) one or more excipients selected from sugars and sugar alcohols,
It provides a freeze-dried preparation containing.
<Formula 1>
However, when the pH adjuster is phosphoric acid or salts thereof, the excipient is mannitol is excluded.
Moreover, according to the 2nd aspect of this invention,
An article comprising a container and a lyophilized formulation according to the present invention as described above, wherein the head space of the vessel filled with the lyophilized formulation is nitrogen-substituted.
In addition, the term "article" used by this invention means the container containing the freeze-dried preparation which concerns on this invention, As a specific example of a container, the vial bottle filled with a freeze-dried preparation is mentioned. In addition, in this invention, what melt | dissolved the pH adjuster in water or an aqueous solvent (for example, a mixture of water and alcohol) may be called pH adjustment liquid.
Effect of the Invention
According to the invention, (8E, 12E, 14E) -7-((4-cycloheptylpiperazin-1-yl) carbonyl) oxy-3,6,16,21-tetrahydroxy-6,10,12 Provided is a lyophilized formulation having excellent stability over time and recombination during reconstitution, including, 16,20-pentamethyl-18,19-epoxytricosa 8,12,14-triene-11-oxide.
Best Mode for Carrying Out the Invention
The following embodiment is an illustration for demonstrating this invention, and is not intended to limit this invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist of the invention.
(Compound represented by Formula 1 or a pharmacologically acceptable salt thereof)
Compound represented by formula (1) used in the present invention ((8E, 12E, 14E) -7-((4-cycloheptylpiperazin-1-yl) carbonyl) oxy-3,6,16,21-tetrahydroxy -6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-triene-11-oxide) is synthesized by the method described in International Publication WO03 / 099813. It may be used or may be used as it is or may be used as a pharmacologically acceptable salt thereof.
<Formula 1>
Although the term "pharmacologically acceptable salt" used in the present invention is not particularly limited, salts with acids such as hydrochloride, sulfate, phosphate, citrate, tartarate, methanesulfonate, ethanesulfonate, brominated Hydrochloride, toluene sulfonate, etc. are mentioned.
The freeze-dried preparation (hereinafter, simply referred to as "the present freeze-dried preparation") according to the present invention contains a compound represented by the formula (1) or a pharmacologically acceptable salt thereof as an active ingredient, and a compound represented by the formula (1) The content in one vial of its pharmacologically acceptable salt is usually 0.1 to 100 mg, preferably 0.2 to 75 mg, more preferably 0.4 to 50 mg, still more preferably 0.5 to 30 mg.
(PH adjuster which adjusts pH in preparation to 5-8)
The pH adjuster for adjusting the pH of the freeze-dried preparation is to adjust the pH of the aqueous solution provided for freeze drying to 5 to 8, preferably pH 5.4 to 7.6, more preferably 5.8 to 7.2. The pH adjuster for adjusting the pH in the formulation to 5 to 8 is not particularly limited as long as it is generally used in pharmaceutical preparations. For example, citric acid or salts thereof (such as sodium citrate), tartaric acid or salts thereof (such as sodium tartrate) , Phosphoric acid or salts thereof (sodium dihydrogen phosphate, sodium monohydrogen phosphate, etc.), carbonic acid or salts thereof (sodium carbonate, sodium hydrogen carbonate, etc.), lactic acid or salts thereof (such as sodium lactate), acetic acid or salts thereof (such as sodium acetate) , Meglumine, sodium hydroxide and the like. Preferably it is citric acid or its salt (sodium citrate etc.), tartaric acid or its salt (sodium tartarate etc.), phosphoric acid or its salt (sodium dihydrogen phosphate, sodium monohydrogen phosphate etc.), More preferably, citric acid or its salt ( Sodium citrate, etc.), and the pH in the formulation can be adjusted to 5 to 8 by using aqueous solutions such as sodium hydroxide and hydrochloric acid. In addition, as mentioned above, although the salt in a pH adjuster illustrated the sodium salt, the pH adjuster used by this invention is not limited to this, A potassium salt etc. are included.
Although the compounding quantity of a pH adjuster is not specifically limited, Usually, it is 0.1-300 weight part with respect to 1 weight part of compounds represented by General formula (1), Preferably it is 0.2-200 weight part, More preferably, it is 0.3-100 weight part More preferably, it is 0.3-50 weight part.
(At least one excipient selected from sugars and sugar alcohols)
The excipient used in the lyophilized formulation is at least one or more excipients selected from sugars and sugar alcohols. The sugars are not particularly limited, but for example, glucose, fructose and the like as monosaccharides, maltose, lactose, sucrose, trehalose and the like as disaccharides. Examples of sugar alcohols include mannitol, erythritol, inositol, sorbitol and the like.
Among the sugars and sugar alcohols, in particular, excipients present as amorphous powders in lyophilized formulations are preferred because of the large stabilizing effect of the compound represented by the formula (1) or a pharmacologically acceptable salt thereof. Specific examples of the monosaccharides include glucose and fructose, disaccharides such as maltose, lactose, sucrose and trehalose, and sugar alcohols such as inositol and sorbitol, and preferably sucrose.
In the lyophilized formulation, when the excipient contains two or more excipients selected from sugars and sugar alcohols, at least 40% by weight or more of the excipient present as an amorphous powder in the lyophilized formulation, based on the total weight of the excipient. Preferably it is 50 weight% or more, More preferably, it contains 60% or more.
The amount of one or more excipients selected from sugars and sugar alcohols in the present lyophilized formulation is 2 to 1500 parts by weight, preferably 4 to 1000 parts by weight, more preferably 1 part by weight of the compound represented by the formula (1). Preferably from 6 to 500 parts by weight, more preferably from 10 to 300 parts by weight.
The lyophilized formulations are at least one selected from 1) a compound represented by formula (1) or a pharmacologically acceptable salt thereof, 2) a pH adjuster for adjusting the pH of the formulation to 5 to 8, and 3) a saccharide and a sugar alcohol. In addition to the excipient, it further contains at least one stabilizer selected from cyclodextrins, glycine and polyethylene glycol.
The cyclodextrins of the stabilizer used in the present invention are not particularly limited, but for example, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, partially methylated β-cyclodextrin, dimethyl-β-cyclodextrin, glycosyl -β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, preferably β-cyclodextrin, γ-cyclodextrin, partially methylated β-cyclodextrin, dimethyl- β-cyclodextrin, glycosyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, more preferably β-cyclodextrin, dimethyl-β-cyclodextrin, hydroxy Propyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin, and more preferably hydroxypropyl-β-cyclodextrin.
Although the polyethyleneglycol of the stabilizer used for this invention is not limited to the thing of a specific molecular weight, For example, polyethyleneglycol 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3250, 3350, 3500, 3750, 4000, 4250, 4500, 4750, 5000, 5500, 6000, 6500, 7000, 7500, 8000 etc. are mentioned. Polyethylene glycol has a very good stabilizing effect with respect to the compound represented by the general formula (1) irrespective of the magnitude of the molecular weight, but in the case of use in the injection, there are many low molecular weight polyethylene glycol, and as a characteristic of the freeze-drying technique In consideration of being easy to freeze-dried as much as a high molecular weight additive, Preferably it is polyethyleneglycol 700, 800, 900, 1000, 800, 1000, etc., More preferably, it is polyethyleneglycol 600.
Although the compounding quantity of a stabilizer is not specifically limited, Usually, it is 0.2-500 weight part with respect to 1 weight part of compounds represented by General formula (1), Preferably it is 0.4-400 weight part, More preferably, it is 0.6-300 weight part More preferably, it is 1-100 weight part.
The lyophilized formulation further comprises an antioxidant. In the present invention, in addition to 1) a compound represented by the formula (1) or a pharmacologically acceptable salt thereof, 2) a pH adjuster for adjusting the pH of the formulation to 5 to 8, and 3) at least one excipient selected from saccharides and sugar alcohols And freeze-dried preparations containing antioxidants. Since a small amount of the oxidant of the compound represented by General formula (1) may be produced, the production | generation of this oxidant is suppressed by addition of antioxidant.
The antioxidant is not particularly limited as long as it is commonly used in pharmaceutical preparations. Examples thereof include L-cysteine hydrochloride, sodium nitrite, ascorbic acid, citric acid, tocophenol, tocophenol acetate, dibutylhydroxytoluene, sodium hydrogen sulfite, Alphathioglycerine, sodium thioglycolate, etc. are mentioned.
Surfactant, a penetration control agent, a preservative, etc. can also be added to this lyophilized formulation further. As the surfactant, polysorbate, polyoxyethylene polyoxypropylene glycol, polyethylene-cured castor oil, sesquioleic acid sorbitan, and the like; glucose, xylitol, sorbitol, and the like as preservatives; benzoic acid, ascorbic acid, and the like; Although these are mentioned, It is not limited to these.
In addition, the lyophilized formulation is selected from 1) a compound represented by the formula (1) or a pharmacologically acceptable salt thereof, 2) a pH adjusting agent for adjusting the pH in the formulation to 5 to 8, and 3) a sugar and a sugar alcohol. It is a lyophilized preparation containing at least one excipient, and adding at least one stabilizer selected from cyclodextrins, glycine and polyethylene glycol, antioxidants and the like, wherein the head space of the filled vial bottle is nitrogen-substituted.
The lyophilized formulation can control its initial water content by controlling the drying time and drying temperature of the freeze drying process. The initial stage moisture content of this lyophilized formulation is usually 2.0% or less, preferably 1.7% or less, and more preferably 1.5% or less.
This lyophilized formulation has the property of being very excellent in the stability over time and the solubility during reconstitution of the compound represented by the formula (1) or a pharmacologically acceptable salt thereof in the formulation. The lyophilized formulations are at least one selected from 1) a compound represented by formula (1) or a pharmacologically acceptable salt thereof, 2) a pH adjuster for adjusting the pH of the formulation to 5 to 8, and 3) a saccharide and a sugar alcohol. By lyophilization with an excipient, a lyophilized formulation excellent in stability over time and excellent in solubility at reconstitution can be obtained. In particular, in the lyophilized formulation, when an excipient present as an amorphous powder is used, especially when citric acid and its salt are used as the pH adjusting agent, the stabilizing effect is also large. Moreover, stability is further improved by adding cyclodextrins, glycine, or polyethylene glycol as a stabilizer. In addition, the combination of an antioxidant and nitrogen replacement of the head space of the vial bottle filled with the freeze-dried preparation contribute to the stability improvement of the freeze-dried preparation.
This lyophilized formulation can be manufactured by the following method, for example. Specifically, 1) a compound represented by the formula (1) or a pharmacologically acceptable salt thereof, 2) a pH adjuster for adjusting the pH of the formulation to 5 to 8, and 3) one or more excipients selected from sugars and sugar alcohols, And, if necessary, a solution obtained by dissolving a stabilizer, an antioxidant, or the like in water or a suitable aqueous solvent (for example, a mixture of water and an alcohol) is filtered and sterilized using a membrane filter or the like as necessary. Subsequently, the sterile solution is dispensed into a vial bottle, a tray or the like, and is preferably made into a solid powder by ordinary freeze drying.
In the freeze-dried preparation prepared as described above, degradation of the compound represented by the formula (1) or its pharmacologically acceptable salts with time is suppressed, and the stability and solubility in reconstitution are excellent.
When preparing the above-mentioned solution, according to a known method, the compound represented by the formula (1) or a pharmacologically acceptable salt, excipient and pH adjusting agent thereof is added to water or an aqueous solvent (for example, a mixture of water and alcohol). It can melt | dissolve (The solution which melt | dissolved is hereafter called "aqueous solution."). The order of dissolution is not particularly dependent on the type of the component, and can be dissolved arbitrarily. However, since the compound represented by the formula (1) or its pharmacologically acceptable salt thereof has excellent solubility in the low pH range, a pH adjuster is used. Thus, to prepare a low pH (5 to 7) adjustment solution to inhibit the decomposition of the compound represented by the formula (1) or pharmacologically acceptable salt thereof, and after dissolving the compound represented by the formula (1) or a pharmacologically acceptable salt thereof It is preferable to adjust to predetermined pH. In addition, in order to prevent the compound represented by the formula (1) or a pharmacologically acceptable salt thereof from being decomposed in an aqueous solution, it may be prepared by keeping the solution temperature during the preparation at a low temperature. The concentration of the compound represented by the formula (1) or a pharmacologically acceptable salt thereof in the aqueous solution is usually 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 5 mg / mL, more preferably 0.5 mg / mL to 2 mg / mL.
In addition, the concentration of the excipient in the aqueous solution is usually 10 mg / mL to 200 mg / mL, preferably 20 mg / mL to 175 mg / mL, and more preferably 30 mg / mL to 150 mg / mL.
In addition, the pH of the aqueous solution provided for lyophilization is 5 to 8, preferably pH 5.4 to 7.6, more preferably 5.8 to 7.2. By adding the pH adjuster mentioned above suitably, it can adjust to desired pH.
The aqueous solution thus prepared is preferably pre-frozen at the process point and below the glass transition point, and then the shelf temperature is gradually raised to the primary drying temperature while maintaining the interior of the drying chamber under vacuum, followed by primary drying at the same temperature. Run After completion of the primary drying, the shelf temperature is further elevated until the secondary drying temperature is reached, and secondary drying is performed at the same temperature.
A method for preparing a specific lyophilized formulation, comprising: 1) a compound represented by formula (1) or a pharmacologically acceptable salt thereof, 2) a pH adjuster for adjusting the pH of the formulation to 5 to 8, and 3) a saccharide and a sugar alcohol After sterilizing the aqueous solution further containing one or more excipients, and stabilizing agents, antioxidants, etc., if necessary, a predetermined amount is dispensed into the vial bottle. Preliminary freezing is carried out under the conditions of about -60 ° C to -20 ° C, followed by primary drying under reduced pressure at about -20 ° C to 20 ° C, secondary drying under reduced pressure at about 10-40 ° C, and freeze drying. Then, if necessary, the head space of the vial bottle is replaced with nitrogen gas and wired to obtain a freeze-dried preparation. In addition, at the time of preliminary freezing, it is necessary to keep it at low temperature which does not become a temperature above a process point and a glass transition point so that crystallization of an excipient may not arise. The process point and the glass transition point depend on the mixing ratio of the components constituting the excipient, but usually the temperature conditions of the preliminary freezing in the case of containing sugars and sugar alcohols, for example, sucrose and / or lactose, It is usually preferable to carry out at a temperature of -40 deg.
Since the excipient is present as an amorphous powder, the lyophilized formulation thus obtained can maintain stability over time.
In addition, the lyophilized formulations have good reconstitution properties. That is, it can be redissolved very easily by addition of arbitrary suitable solutions (resolution solution), and can rebuild the solution before freeze drying. Such redissolved solutions include distilled water for injection, physiological saline, and other common sap (e.g., glucose, amino acid sap, etc.).
The solution of the redissolved lyophilized formulation can be administered parenterally as an injection or eye drop such as an intravenous injection, a subcutaneous injection, an intramuscular injection, a drop injection, or the like. The solution dissolved in distilled water for injection, physiological saline solution or sap is sufficiently stable. The concentration of the compound represented by the formula (1) or its pharmacologically acceptable salt in the reconstitution and dilution is usually 0.001 mg / mL to 10 mg / mL, and preferably 0.005 mg / mL to 5 mg / mL.
Although an Example and a comparative example of the present invention shown below are given and this invention is demonstrated in more detail, these are illustrative and this invention is not restrict | limited to the following examples. Those skilled in the art can make the present invention by adding various changes to the Example shown below, and such a change is included in a claim of this application.
Examples of the additives described in the following Examples were those suitable for the procedures such as Japanese Pharmacopoeia IV, Pharmaceutical Additives Standard 2005 (Drug Addendum), Japanese Pharmacopoeia Pharmaceutical Standards (Foreign Substance) 2005, USP / NF XXIII, or a reagent.
Preparation Example 1 (investigation of the type of pH regulator, the type of one or more excipients selected from sugars and sugar alcohols, and the amount thereof)
(Reference Example 1 and Examples 1 to 6)
The lyophilized formulations of Reference Example 1 and Examples 1 to 6 of the present invention may be one or more selected from a pH adjuster for adjusting the pH of the formulation of the compound represented by the formula (1) to 5 to 8, and sugars and sugar alcohols. The kind and excipient of an excipient were changed, and it manufactured by the following method.
50 mM containing a sugar or sugar alcohol by dissolving a predetermined amount of citric acid monohydrate or phosphoric acid in distilled water for injection and dissolving a predetermined amount of excipients of mannitol, sucrose or lactose, while adjusting the pH using a sodium hydroxide solution. Or 50 mL of 100 mM pH adjuster (pH 6) was prepared.
Next, 6 mg of the compound represented by the formula (1) was dissolved (1 mg / mL) in 6 mL of these solutions, and then 1 mL of the filter filtered solution (0.22 μm filter) was subdivided into vials and lyophilized. The freeze-dried vial was nitrogen-substituted in its head space and wired with a rubber stopper, then wrapped in an aluminum cap to obtain the present freeze-dried formulation as Reference Examples 1 and Examples 1 to 6 (Table 1). In addition, the amount of the pH adjuster in the formulation filled in one vial was equivalent to 50 mM of 4.9 mg of phosphoric acid (Reference Examples 1 and 2) or 10.5 mg of citric acid monohydrate (Examples 3 to 5), and citric acid monohydrate. 21.0 mg (Example 6) corresponded to 100 mM.
Also as controls, Controls 1 and 2 were prepared. In Comparative Example 1, 1 mg of the compound represented by the formula (1) was measured, and the vial was filled in its powder state, and its head space was nitrogen-substituted and wired with a rubber stopper. Comparative Example 2 includes a compound represented by the formula (1) prepared in the same manner as Examples 3 to 5 and a pH adjuster for adjusting the pH in the formulation to about 6 except adding a predetermined amount of excipients of mannitol, sucrose or lactose It is a lyophilized formulation.
Moreover, the physical property value of the manufactured formulation was evaluated. The evaluation items were the amount of impurity increase derived from the compound represented by the formula (1) after two weeks of storage under physical properties upon reconstitution immediately after preparation and 75% at 40 ° C relative humidity.
Evaluation of physical properties at the time of reconstitution immediately after preparation was reconstituted by adding 1 ml of distilled water for injection and physiological saline to the lyophilized formulation filled in one vial, and the reconstruction property was evaluated by the Sumiri C method. The Sumimori C method is a method described in [Pharmaceutical Plant p574, Vol. 6, No. 6, 1986], and is one method of evaluating the reconstitution property of a dissolution injection in use.
At the same time, the solution pH of the reconstituted formulation was evaluated.
Evaluation of the impurity increase amount after 2-week storage at 40 degreeC relative humidity 75%, The amount of impurity in the preparation immediately after manufacture, and the impurity amount of the preparation preserve | saved for 2 weeks at 40 degreeC relative humidity 75% are evaluated by high performance liquid chromatography, respectively. It is shown as the amount (%) increased compared with the amount of impurities in the preparation immediately after preparation. Representative HPLC conditions are shown below.
Column: L-column ODS (4.6 × 150 mm, 5 um, Chemical Evaluation Research Organization)
Column temperature: 40 ℃
Detector: UV / PDA (detection wavelength 241 nm)
Mobile phase A: acetonitrile / purified water / potassium dihydrogen phosphate / sodium perchlorate (500 mL / 4500 mL / 1.0 g / 35 g)
Mobile phase B: acetonitrile / purified water / sodium perchlorate (4500 mL / 500 mL / 35 g)
Flow rate: 1 mL / min
Sample solution: 20% acetonitrile
Sample cooler: 5 ℃
Injection volume: 10 uL (0.2 mg / mL)
Gradient program: B28% (0 minutes)-B28% (15 minutes)-B100% (20 minutes)-B28% (25.01 minutes)-B28% (33 minutes)
In addition, the impurity increase amount was expressed as both the increase amount (%) of the total amount of impurities and the increase amount of the main impurities A by decomposition of the compound represented by the formula (1). The main impurity A is assumed to be either one of the two compounds represented by the formula (2) or a mixture of both.
Table 1 shows the composition and physical properties of the lyophilized formulations of Reference Example 1 and Examples 2 to 6.
Production Example 2 (Review of Kinds of Sugars Existing as Amorphous Powder)
(Examples 7 to 8)
The freeze-dried preparations of Examples 7 to 8 of the present invention are one or more excipients selected from sugars and sugar alcohols formulated in the compound represented by Formula 1, and change the type of sugars present as amorphous powder in the freeze-dried preparations. It manufactured by the following method.
A 50 mM pH adjustment liquid containing saccharides by dissolving a predetermined amount of citric acid monohydrate in distilled water for injection, adjusting a pH using a sodium hydroxide solution, and dissolving a predetermined amount of excipients of sucrose, trehalose, or maltose. 50 mL (pH 6) was prepared. Next, 6 mg of the compound represented by the formula (1) was dissolved (1 mg / mL) in 6 mL of these solutions, and then 1 mL of the filter filtered solution (0.22 μm filter) was subdivided into vials and lyophilized. The freeze-dried vial was nitrogen-substituted in its head space and wired with a rubber stopper, then wrapped in an aluminum cap to obtain this freeze-dried formulation as Examples 4, 7, and 8 (Table 2). In addition, the amount of pH adjuster in the formulation filled in one vial was 10.5 mg of citric acid monohydrate (Examples 4, 7, 8) and the amount of excipient of sucrose, trehalose, or maltose was 100 mg.
In addition, the physical property value of the manufactured formulation performed the same evaluation by the method of manufacture example 1. Table 2 shows the formulations and physical properties of the lyophilized formulations of Examples 4, 7, and 8.
Production Example 3 (Inspection of Stabilizer, Polyethylene Glycol Type (Molecular Weight) and Addition Amount)
(Examples 9 to 16)
The lyophilized formulations of Examples 9 to 16 of the present invention comprise 1) a compound represented by Formula 1, 2) a pH adjuster (using citric acid monohydrate) to adjust the pH in the formulation to 5-8, and 3) sugars and sugars. As a stabilizer formulated into a lyophilized formulation comprising one or more excipients selected from alcohols (using sucrose), the type and amount of addition thereof are varied to prepare the following method.
A predetermined amount of citric acid monohydrate was dissolved in distilled water for injection, and a predetermined amount of sucrose and a stabilizer were dissolved while adjusting the pH using a sodium hydroxide solution, and a 50 mM pH adjusting liquid containing sucrose and a stabilizer (pH 6 ) 50 mL was prepared.
Next, 6 mg of the compound represented by the formula (1) was dissolved (1 mg / mL) in 6 mL of these solutions, and then 1 mL of the filter filtered solution (0.22 μm filter) was subdivided into vials and lyophilized. The lyophilized vial was replaced with nitrogen by replacing its head space with a rubber stopper and wrapped in an aluminum cap, followed by Examples 9-11 (Table 3), Examples 12-14 (Table 4) and Examples 15-16 (Table). As 5), this lyophilized formulation was obtained.
In addition, the amount of pH adjuster in the formulation filled in one vial was 10.5 mg of citric acid monohydrate (Examples 9 to 16), and the amount of excipient of sucrose was 100 mg. As stabilizers 10 mg of hydroxypropyl-β-cyclodextrin, glycine, and polyethylene glycol 4000 in vials of lyophilized formulations, respectively, were contained in Examples 9-11. In Examples 12-14, the kind (molecular weight) of polyethyleneglycol was changed as a stabilizer, and 10 mg was contained in the freeze-dried preparation of the vials containing polyethyleneglycol 400, polyethyleneglycol 600, and polyethyleneglycol 4000, respectively. In Examples 15, 13, and 16, the amount of polyethylene glycol 600 added as a stabilizer was changed to contain 5 mg, 10 mg, and 20 mg, respectively, in one vial of lyophilized formulation.
In addition, the physical property value of the manufactured formulation performed the same evaluation by the method of manufacture example 1. The lyophilized formulation formulations and physical properties of Examples 9 to 11, Examples 12 to 14, and Examples 15 to 16 are shown in Tables 3, 4, and 5, respectively.
Preparation Example 4
(Investigation of pH in Formulation by Adding pH Adjuster)
(Examples 17 to 21)
The freeze-dried preparations of Examples 17 to 21 of the present invention were prepared by the following method by changing the pH in the preparation with the pH adjusting agent to be blended.
A predetermined amount of citric acid monohydrate was dissolved in distilled water for injection, and a predetermined amount of sucrose and polyethylene glycol 600 (stabilizer) were dissolved while adjusting the pH using a sodium hydroxide solution. 50 mL of various pH adjusters (pH 5.5, 5.7, 5.9, 6.1, 6.3) were prepared. Next, 6 mg of the compound represented by the formula (1) was dissolved (1 mg / mL) in 6 mL of these solutions, and then 1 mL of the filter filtered solution (0.22 μm filter) was subdivided into vials and lyophilized. The freeze-dried vial was nitrogen-substituted in its head space and wired with a rubber stopper, then wrapped in an aluminum cap to obtain this freeze-dried formulation as Examples 17 to 21 (Table 6). The amount of pH adjuster in the formulation filled in one vial was 10.5 mg of citric acid monohydrate (Examples 18 to 22), the amount of excipient of sucrose was 100 mg, and the amount of polyethylene glycol 600 of the stabilizer was 20 mg. In addition, the physical property value of the manufactured formulation performed the same evaluation by the method of manufacture example 1.
The lyophilized formulation formulations and the physical properties of Examples 17 to 21 are shown in Table 6.
Moreover, the influence which the pH in the preparation by addition of a pH adjuster has on the solubility of the compound represented by General formula (1) was examined.
0.525 g of citric acid monohydrate was dissolved in distilled water for injection, and 5 g of sucrose and 1 g polyethylene glycol 600 (stabilizer) were dissolved while adjusting the pH using a sodium hydroxide solution to contain sucrose and a stabilizer. 50 mL of 50 mM of various pH adjusting solutions (pH 5.6, 5.8, 6.0, 6.2, 6.4, 6.6) were prepared. 3 mL of the prepared pH adjusting solution was added to about 9 mg of the compound represented by the formula (1) in 5 mL vials, and stored at 5 ° C. for 1 hour while stirring with a stirrer. The solution (containing the suspension) was then subjected to filter filtration (0.22 μm filter), to the solution obtained after discarding 1 mL of the initial effluent, and the concentration of the compound represented by the formula (1) by high performance liquid chromatography (HPLC). Was measured and taken as the solubility of the compound represented by General formula (1). In addition, the pH of the solution was also measured at the same time. The results are shown in Table 7.
Production example 5 (nitrogen substitution examination of head space of vial bottle)
(Examples 22 to 23)
The freeze-dried preparations of Examples 22 to 23 of the present invention were prepared by the following method by changing the presence or absence of nitrogen substitution in the head space of the vial bottle.
2.1 g of citric acid monohydrate was dissolved in about 140 mL of distilled water for injection, and the pH was adjusted to 5.6 using sodium hydroxide solution. While cooling this solution to 2-10 degreeC, 20 g of sucrose, 4 g of polyethyleneglycol 600, and 200 mg of the compound represented by General formula (1) were dissolved. The solution was adjusted to pH 6.1 with sodium hydroxide solution, and then the total amount was 200 mL with distilled water for injection. Next, these solutions were filtered by a filter (0.22 µm filter), and the solutions were subdivided into vials each by 1 mL and lyophilized.
The freeze-dried vial was divided into two kinds of head-substituted nitrogen-substituted and ordinary air-substituted ones, wired with a rubber stopper, and wrapped in an aluminum cap, respectively, in Examples 22 and 23 (Table 8). ), This lyophilized formulation was obtained. The amount of pH adjuster in the formulation filled in one vial was 10.5 mg of citric acid monohydrate, the amount of excipient of sucrose was 100 mg, and the amount of polyethylene glycol 600 of the stabilizer was 20 mg.
Moreover, the physical property value of the manufactured formulation was evaluated. The evaluation items were the amount of impurity increase after storage for 2 weeks under the initial moisture content immediately after preparation and 75% of 40 ° C relative humidity. The initial moisture content was evaluated using a curling fischer moisture meter (Mitsubishi Chemical Industries, Ltd.) based on Japanese Pharmacopoeia IV.
The lyophilized formulation formulations and the physical properties of Examples 22 to 23 are shown in Table 8.
Preparation Example 6 (antioxidant addition study)
(Examples 24 to 27)
The freeze-dried preparations of Examples 24 to 27 of the present invention were prepared by the following method with varying amounts of antioxidants added.
1) 1 mg of the compound represented by Formula 1, 2) 10.5 mg of pH adjuster for adjusting the pH of the formulation to 6.1 (using 50 mM citric acid monohydrate), 3) at least one excipient 100 selected from sugars and sugar alcohols mg (using sucrose), and 4) an antioxidant was added to the composition containing 20 mg (polyethylene glycol 600) stabilizer, and the influence on the stability of the compound represented by General formula (1) was examined. In addition, L-cysteine hydrochloride monohydrate was used as an antioxidant, and the addition amount in the formulation was made into 4 levels of 0 mg (not added), 0.01 mg, 0.05 mg, and 0.10 mg.
That is, 0.525 g of citric acid monohydrate is dissolved in distilled water for injection, and the pH is adjusted using a sodium hydroxide solution, while additionally 5 g of sucrose and 1 g of polyethylene glycol 600 and a predetermined amount (0 g, 0.005 g, respectively). , 0.0025 g, 0.0005 g) of L-cystine hydrochloride monohydrate was dissolved to prepare 50 mL of 50 mM pH adjuster (pH 6.1) containing sucrose, polyethylene glycol 600, and L-cystine hydrochloride monohydrate. Next, 6 mg of the compound represented by the formula (1) was dissolved (1 mg / mL) in 6 mL of these solutions, and then 1 mL of the filter filtered solution (0.22 μm filter) was subdivided into vials and lyophilized. The freeze-dried vial was nitrogen-substituted in its head space and wired with a rubber stopper, then wrapped in an aluminum cap to obtain this freeze-dried formulation as Examples 25 to 28 (Table 9).
Moreover, the physical property value of the manufactured formulation was evaluated. The evaluation item is the amount of impurity increase after two weeks of storage under 75% of 40 ° C relative humidity. In addition, the impurity increase amount is a ratio of the total amount increase amount (%) of the initial impurity immediately after preparation to the amount of the oxidant by oxidative decomposition of the compound represented by the formula (1), and the total amount of the increased impurity and the compound represented by the formula (1) Both amounts of increased oxidant by oxidative degradation are shown.
The lyophilized formulation formulations and physical properties of Examples 24 to 27 are shown in Table 9.
Production Example 7 (investigation of moisture content of freeze-dried preparation)
The effect of the moisture content in the lyophilized formulation on the stability of the compound represented by the formula (1) was examined. First, the vial (pH 6.23) prepared by nitrogen substitution in Example 20 was opened, and the moisture was absorbed while monitoring the weight change under humidity, and then each moisture value was measured by a curling fischer moisture meter. %) (5 levels of 0.48%, 0.66%, 1.20%, 1.64%, 2.19%). About these, the rubber stopper was further wired and wrapped, and it was set as the sample which has each initial water content. About these samples, it preserve | saved for 2 weeks under 75% of 40 degreeC relative humidity, and evaluated the increase amount of an impurity.
Lyophilized formulation formulations and physical properties are shown in Table 10.
When the initial moisture value of the preparation exceeded 1.5%, decomposition tended to accelerate.
Effect of the Invention
According to the present invention, it is possible to prepare a lyophilized formulation which is excellent in stability over time including the compound represented by the formula (1) and excellent in solubility during reconstitution.
1. Effect on stability and reconstitution properties of a lyophilized formulation comprising a pH adjusting agent, excipients such as sugars and sugar alcohols, and a compound represented by the formula (1) (Preparation Example 1, Preparation Example 2)
In the formulation prepared as a control example in Preparation Example 1 shown in Table 1, the compound represented by the formula (1), which is a crystal in the powder-filled formulation (Comparative Example 1), was stable, but the reconstruction property was remarkably bad and did not dissolve. In addition, in the freeze-dried preparations containing the compound represented by the formula (1) of the comparative example 2 and the pH adjuster for adjusting the pH in the preparation to 6, sufficient reconstitution properties were obtained for the injection, but impurity A and impurities as main decomposition products were obtained. An increase in the total amount of was recognized.
Meanwhile, the preparations according to Examples 1 to 6 of Preparation Example 1 of the present invention are selected from 1) a compound represented by the formula (1), 2) a pH adjusting agent for adjusting the pH in the preparation to 6, and 3) sugars and sugar alcohols. It is a lyophilized formulation containing one or more excipients, and by combining an excipient other than mannitol, an increase in the total amount of impurities A and impurities, which are main decomposition products, is suppressed as compared with Comparative Example 2, and the stability is improved, and the reconstitution properties are also good. It was.
Its stabilizing effect is remarkably excellent in sugars (excipients) present as amorphous powder, except for formulations containing mannitol (Reference Example 1, Example 3), especially when sucrose is used as an excipient (Example 4). Moreover, when citric acid monohydrate (10.5 mg: Example 5, 21.0 mg: Example 6) was used as a pH adjuster, there exist especially a high decomposition inhibitory effect, and especially production of the impurity A which is a main decomposition product was remarkably suppressed.
The preparations according to Examples 7 to 8 of Preparation Example 2 of the present invention shown in Table 2 are freeze-dried preparations each containing trehalose and maltose, which are saccharides present as amorphous powder in freeze-dried preparations, similarly to sucrose. In all cases, as in Example 4, the increase in the total amount of the impurity A and the impurities, which are the main decomposition products, was suppressed, and the stability was improved.
Stability and reconstitution of a lyophilized formulation comprising a compound represented by the formula (1) in which a pH adjuster for adjusting the pH in a formulation such as citric acid monohydrate to 5 to 8, excipients such as sugars and sugar alcohols, in particular, sugars present as amorphous powders It is clear that the characteristics are improved.
2. Effect on the Stability and Reconstitution Characteristics of Lyophilized Formulations Containing Stabilizers (Preparation Example 3)
Formulations according to Examples 9 to 16 of Preparation Example 3 of the present invention are 1) a compound represented by the formula (1), 2) a pH adjuster (using citric acid monohydrate) to adjust the pH in the formulation to 5 to 8, and 3) A stabilizer formulated into a lyophilized formulation comprising one or more excipients (using sucrose) selected from saccharides and sugar alcohols, wherein the type and amount thereof were changed.
As shown in Table 3, the stabilizing effect was confirmed in the addition of hydroxypropyl-β-cyclodextrin (Example 9), glycine (Example 10), polyethylene glycol (Example 11) and the like as a stabilizer. . In particular, addition of polyethylene glycol 4000 (molecular weight 3350) (Example 11) showed remarkable suppression of the generation of impurity A as a main decomposition product, and the reconstitution property was also good. Moreover, the relationship between the kind (molecular weight 400, 600, 4000) and the stabilizing effect was examined about the polyethylene glycol which was the most excellent stabilizing effect (Examples 12-14). As a result, also in the addition of polyethylene glycol of any molecular weight, decomposition of the compound represented by the formula (1) was suppressed (Table 4). In particular, polyethylene glycol 600 was excellent in the stabilizing effect.
In addition, the relationship between the addition amount and the stabilizing effect of the polyethylene glycol 600 was examined, and as shown in Table 5, polyethylene glycol 600 (molecular weight 600) suppressed decomposition of the compound represented by the formula (1) depending on the addition amount, In particular, the inhibition of the production of impurity A, the main degradation product, was shown.
By the addition of the stabilizer in the present freeze-dried formulation, it was proved that, in particular, by addition of polyethylene glycol or the like, the stability of the freeze-dried formulation can be improved and a good reconstitution property can be ensured depending on the addition amount.
3. Effect on the Stability (Preparation Example 4) and Solubility of the Compound of Formula 1 by pH in Formulation by Addition of pH Adjuster
As for the formulations of Examples 17 to 21 of Preparation Example 4 of the present invention, as shown in Table 6, the pH of the lyophilized formulation containing the compound represented by the formula (1) was adjusted using citric acid monohydrate of the pH adjusting agent, respectively. It was a formulation adjusted to pH 5.5, 5.7, 5.9, 6.1, 6.3. Above pH 5.5, as the pH was increased, decomposition of the compound represented by the formula (1) was suppressed and stabilization appeared.
Moreover, the influence which the pH in the preparation by addition of a pH adjuster has on the solubility of the compound represented by General formula (1) was examined. As a result, as shown in Table 8, in pH 5.79-7.04, although solubility was high in the low pH area | region, solubility fell remarkably in the high pH area | region. The pKa of the compound represented by the general formula (1) is about 7.9, solubility decrease to around pH 8 is remarkable, and the pH range which can be used as an injection is limited in terms of solubility, so it is necessary to ensure sufficient solubility.
Since the pH (5-8) in the formulation by the pH adjuster in the present freeze-dried formulation affects the stability and solubility of the compound represented by the formula (1), the freeze-drying is performed by adjusting the pH in the formulation by balance of stability and solubility. It has been found that it is possible to improve the stability of the formulation and to ensure good reconstitution properties.
4. Effect on the Stability of the Compound of Formula 1 with or Without Nitrogen Substitution in the Head Space of Vial Bottles (Preparation Example 5)
About the lyophilized formulation of the compound represented by General formula (1), the influence of the presence or absence of nitrogen substitution of the head space of a vial bottle on the stability of the compound represented by General formula (1) in a formulation was examined. As a result, as shown in Table 8, when the moisture values at the beginning of manufacture were almost the same or when nitrogen was substituted (Example 22), decomposition was significantly suppressed as compared with when nitrogen was not substituted (Example 23). .
By performing nitrogen replacement of the head space of the vial bottle filled with the lyophilized formulation, it has been found that the stability of the lyophilized formulation can be improved and good reconstitution properties can be ensured.
5. Effect on the Stability of the Compound of Formula 1 by Addition of Antioxidant (Preparation Example 6)
As shown in Table 9, the lyophilized formulation of the compound represented by the formula (1) containing the stabilizer showed that an oxidant was produced at the time point immediately after preparation, and it increased during the stability test. Particularly, in the system containing polyethylene glycol, an increase in the amount of oxidants at the beginning of the production and an increase in the total amount of impurities were observed (Example 24). On the other hand, in the system to which L-cysteine hydrochloride monohydrate was added as an antioxidant, the addition of trace amount suppressed the increase of the amount of oxidized body and the increase of the total amount of impurities accordingly (Examples 25 to 27).
It was proved that the present freeze-dried preparations can improve the stability of the freeze-dried preparations by adding a small amount of an antioxidant, especially when a stabilizer is blended.
6. Effect on the Stability of Compounds of Formula 1 by Moisture Content in Lyophilized Formulations
From the results shown in Table 10, the higher the amount of water in the freeze-dried preparation, the lower the stability of the compound represented by the formula (1), and therefore, it is particularly desirable to maintain the amount of water in the preparation at least 2.0% by weight or less. It was proved that the stability of the lyophilized formulation can be improved by making it necessary and preferably 1.5 weight% or less.
According to the invention, (8E, 12E, 14E) -7-((4-cycloheptylpiperazin-1-yl) carbonyl) oxy-3,6,16,21-tetrahydroxy-6,10,12 Provided is a lyophilized formulation having excellent stability over time and recombination during reconstitution, including, 16,20-pentamethyl-18,19-epoxytricosa 8,12,14-triene-11-oxide.
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| KR1020097003067A KR20090047474A (en) | 2009-02-13 | 2007-08-13 | Stable lyophilized preparation |
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| Application Number | Priority Date | Filing Date | Title |
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| KR1020097003067A KR20090047474A (en) | 2009-02-13 | 2007-08-13 | Stable lyophilized preparation |
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| KR20090047474A true KR20090047474A (en) | 2009-05-12 |
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