CN101695479A - Instant pirarubicin freeze-dried powder injection and preparation method thereof - Google Patents
Instant pirarubicin freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN101695479A CN101695479A CN200910110676A CN200910110676A CN101695479A CN 101695479 A CN101695479 A CN 101695479A CN 200910110676 A CN200910110676 A CN 200910110676A CN 200910110676 A CN200910110676 A CN 200910110676A CN 101695479 A CN101695479 A CN 101695479A
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- pirarubicin
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Abstract
The invention discloses an instant pirarubicin freeze-dried powder injection and a preparation method thereof. The preparation comprises pirarubicin or pharmaceutically acceptable salts thereof, an excipient and a cosolvent, wherein the cosolvent is niacinamide or combination of the niacinamide and other cosolvents. The time for redissolving the instant pirarubicin freeze-dried preparation in physiological saline is shortened to between 5 and 20 seconds, and the redissolution is quicker and easier than the prior art; and stability study proves that the freeze-dried preparation has good stability and is suitable for clinical application.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of instant pirarubicin freeze-dried powder injection and preparation method thereof.
Background technology
Pirarubicin (have another name called Perarubicin, English is abbreviated as THP) is an anthracene nucleus antineoplastic antibiotic of new generation, and its structural formula is as follows:
By the exploitation of Japanese MeijiSeikaKaisha (Meiji Seika Kaisba) Pharmaceutical Co., Ltd, 1988 in Japan's listing, listing at home in 1993.The pirarubicin preparation specification of domestic listing is 10 milligrams and 20 milligrams of injection powder injections.Clinical effectiveness is used and is shown that this medicine all has better curative effect to incidence cancer, gastric cancer, breast carcinoma, ovarian cancer, uterus carcinoma, urothelium cancer, especially bladder cancer, and acute leukemia, malignant lymphoma etc.Pirarubicin is " national essential drugs catalogue ", " national basic medical insurance medicine catalogue " kind, is a line essential drug of oncotherapy.
Those skilled in the art know with the physiological saline solution freeze-dried powder can obtain isoosmotic injection solution, and such solution intravasation and blood etc. are opened, and is more suitable for human body and uses.The hydrochloride for injection pirarubicin freeze-dried powder injection of listing generally all is with water for injection or the dissolving of 5% glucose solution at present, and can not use physiological saline solution, because it is fine that pirarubicin is made after the NSC 654509 in water dissolubility, but its lyophilized formulations solubility in normal saline is very poor, the solution that forms is not clarified, and does not meet the requirement of the clarity of relevant injection in the Chinese Pharmacopoeia.
Those skilled in the art add cosolvent as can be known can improve the dissolubility of insoluble drug in water, and the cosolvent that often uses in bulk capacity injection production is meglumine, organic acid, aminoacid and vitamins.In most of the cases, cosolvent and effective ingredient generation complex reaction generate double salt formula complex soluble in water, and dissolubility is increased.Therefore for different medicines, use which kind of cosolvent to need screening by experiment.
Chinese patent CN85107562 discloses " improving the deliquescent method of a kind of anthracene nucleus glycoside compounds in a kind of injection solution ", promptly add cosolvent and comprise hydroxyl, sulfydryl or amino benzoic acid or its alkali metal salt or its C1-C4 Arrcostab that replaces, or an a kind of ring halogenation methyl substituted phenol or a seed amino acid, for the anthracene nucleus glucosides of per 10 parts of weight, the methyl parahydroxybenzoate that adds 0.1～10 part of weight can solve the solubility of anthracene nucleus glucosides in normal saline of being mentioned.
Disclose the adding organic solvent among the Japan patent of invention JP776515 and can improve the dissolubility of Pirarubicin freeze-dry preparations in normal saline.
Chinese patent ZL200610157023.9 proves that by experiment above-mentioned two technical schemes can not reach ideal effect, and adding hydroxyl, sulfydryl or the amino benzoic acid that replaces or its alkali metal salt or its C1-C4 Arrcostab are disclosed as cosolvent, and pirarubicin for per 10 parts of weight, the cosolvent that adds 0.1～10 part of weight, and use more a spot of methyl parahydroxybenzoate can improve the dissolubility of Pirarubicin freeze-dry preparations in normal saline.This scheme makes the redissolution time of Pirarubicin freeze-dry preparations in normal saline shorten to 20～30 seconds, but still needs repeatedly strong jolting.
Summary of the invention
The technical problem that the present invention solves provides a kind of instant pirarubicin lyophilized formulations and preparation method thereof, and this lyophilized formulations has solubility preferably in normal saline, is fit to clinical use.
A kind of instant pirarubicin lyophilized formulations that provides of the present invention, comprise pirarubicin or its pharmaceutically acceptable salt, excipient and cosolvent, wherein cosolvent is the combination of nicotiamide or nicotiamide and other cosolvent, and the weight ratio of nicotiamide and pirarubicin or its pharmaceutically acceptable salt is 0.01～2: 1;
In the process of screening that various cosolvents are experimentized, we are surprised to find that the solubilization-aid effect of nicotiamide is the most outstanding, use nicotiamide as cosolvent separately, can make the solubility of Pirarubicin freeze-dry preparations in normal saline reach 5 to 20 seconds;
Use separately nicotiamide as cosolvent, the weight ratio of nicotiamide and pirarubicin or its pharmaceutically acceptable salt preferred 0.1～2: 1, most preferably 0.5～1: 1;
By prior art as can be known, hydroxyl, sulfydryl or amino benzoic acid or its alkali metal salt or its C1-C4 Arrcostab that replaces, ring halogenation methyl substituted phenol or aminoacid, the inventor investigates nicotiamide and above-mentioned substance combination as the cosolvent of Pirarubicin freeze-dry preparations, wherein methyl parahydroxybenzoate, phenylalanine, glutamic acid and nicotiamide all can make Pirarubicin freeze-dry preparations that good solubility is arranged in normal saline as cosolvent jointly.
The pirarubicin pharmaceutically acceptable salt can be the salt with mineral acid, for example hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or with organic acid salt, for example acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, Acetic acid,oxo-,monohydrate, pyrovinic acid, ethylsulfonic acid, benzenesulfonic acid, preferred pirarubicin hydrochlorate;
Described excipient adds a kind of suitable inert excipient by prior art as can be known usually except active medicine and cosolvent in the Pirarubicin freeze-dry preparations prescription, for example lactose, mannitol, sorbitol, maltose and dextran, preferably lactose.
More excellent prescription is that to contain each ingredients weight parts in the Pirarubicin freeze-dry preparations be 10 parts of pirarubicin or NSC 654509,50～90 parts of lactose, 5～10 parts of nicotiamide.Optimum prescription is 10 parts of pirarubicin or NSC 654509,80 parts of lactose, 10 parts of nicotiamide.
The preparation method of Pirarubicin freeze-dry preparations of the present invention is as follows: pirarubicin or its pharmaceutically acceptable salt, excipient and cosolvent under agitation are dissolved in an amount of water for injection, the preferred pirarubicin hydrochlorate of pharmaceutically acceptable salt wherein, the preferred lactose of excipient, the preferred nicotiamide of cosolvent, regulate pH value 3.5-6.5 with the PH regulator, the PH regulator is selected dilute hydrochloric acid, 0.22 μ m microporous filter membrane aseptic filtration then, be sub-packed in the cillin bottle, then lyophilization.Lyophilization comprises pre-freeze and sublimation drying, and wherein the pre-freeze temperature of the preceding case of freeze dryer is-35--45 ℃ in the pre-freeze process, insulation, and the temperature of the rear cabinet of freeze dryer is reduced to-50～-60 ℃ between soak; In the sublimation drying process, under the evacuation condition, be warming up to-10 ℃～-40 ℃, exist, heat up again and remove residual moisture until no longer including crystal.Sterilize after the lyophilization, fill nitrogen, obtain freeze-dried powder.
The invention provides a kind of instant pirarubicin lyophilized formulations, the inventor finds that unexpectedly nicotiamide can significantly strengthen the solute effect of pirarubicin in normal saline, therefore used nicotiamide as the cosolvent in the Pirarubicin freeze-dry preparations, need not repeatedly strong jolting just can make the redissolution time of Pirarubicin freeze-dry preparations in normal saline shorten to 5～20 seconds, faster easier than prior art, have good stability through study on the stability proof lyophilized formulations, be fit to clinical use.
Embodiment below in conjunction with the specific embodiment is described in further detail the present invention.
Specific embodiment
Embodiment 1
| Prescription | ??1 | ??2 | ?3 | ??4 |
| Pirarubicin lactose water for injection | 10mg 80mg nicotiamide 1mg 2ml | 10mg 80mg nicotiamide 5mg 2ml | 10mg 80mg nicotiamide 10mg 2ml | 10mg 80mg nicotiamide 20mg 2ml |
| Outward appearance after the lyophilizing | Full better | Full better | Full better | Full better |
| The normal saline solubility | Dissolving in 20 seconds, the solution clarification | Dissolving in 15 seconds, the solution clarification | Dissolving in 5 seconds, the solution clarification | Dissolving in 18 seconds, the solution clarification |
Embodiment 2
| Prescription | ?1 | ??2 | ??3 |
| Pirarubicin lactose cosolvent water for injection | 10mg 90mg nicotiamide 1mg methyl parahydroxybenzoate 4mg 2ml | 10mg 90mg nicotiamide 4mg phenylalanine 2mg 2ml | 10mg 90mg nicotiamide 5mg glutamic acid 2mg 2ml |
| Outward appearance after the lyophilizing | Full better | Full better | Full better |
| The normal saline solubility | Dissolving in 20 seconds, the solution clarification | Dissolving in 15 seconds, the solution clarification | Dissolving in 18 seconds, the solution clarification |
Embodiment 3
| Prescription | ?5 | ?6 | ?7 | ?8 |
| NSC 654509 lactose nicotiamide water for injection | ?10mg ?50mg ?10mg ?2ml | ?10mg ?70mg ?10mg ?2ml | ?10mg ?80mg ?10mg ?2ml | ?10mg ?90mg ?10mg ?2ml |
| Outward appearance after the lyophilizing | Full better | Full better | Full better | Full better |
| The normal saline solubility | Dissolving in 5 seconds, the solution clarification | Dissolving in 5 seconds, the solution clarification | Dissolving in 5 seconds, the solution clarification | Dissolving in 5 seconds, the solution clarification |
Embodiment 4
Adopt above-mentioned preparation method to prepare lyophilized formulations according to following prescription and carry out stability study, the result is as follows:
| Prescription 1 | Prescription 2 | |
| NSC 654509 lactose water for injection nicotiamide | ??10mg ??80mg ??2ml ??5mg | ??10mg ??80mg ??2ml ??10mg |
| 0 day content related substance | ??97.4％ ??0.8％ | ??97.5％ ??0.8％ |
| 5 days content related substances of high temperature | ??97.0％ ??1.0％ | ??97.3％ ??0.9％ |
| 10 days content related substances of high temperature | ??96.8％ ??2.1％ | ??97.2％ ??1.8％ |
As seen from the experiment, add nicotiamide, the having good stability of Pirarubicin freeze-dry preparations as cosolvent.
Claims (10)
1. instant pirarubicin freeze-dried powder injection, it is characterized in that comprising pirarubicin or its pharmaceutically acceptable salt, excipient and cosolvent, wherein cosolvent is the combination of nicotiamide or nicotiamide and other cosolvent, and the weight ratio of nicotiamide and pirarubicin or its pharmaceutically acceptable salt is 0.01～2: 1.
2. a kind of instant pirarubicin freeze-dried powder injection according to claim 1, the weight ratio that it is characterized in that nicotiamide and pirarubicin or its pharmaceutically acceptable salt is 0.1～2: 1.
3. a kind of instant pirarubicin freeze-dried powder injection according to claim 1 and 2, the weight ratio that it is characterized in that nicotiamide and pirarubicin or its pharmaceutically acceptable salt is 0.5～1: 1.
4. a kind of instant pirarubicin freeze-dried powder injection according to claim 1 is characterized in that described pirarubicin pharmaceutically-acceptable salts is the pirarubicin hydrochlorate.
5. a kind of instant pirarubicin freeze-dried powder injection according to claim 1 is characterized in that described excipient is a lactose.
6. a kind of instant pirarubicin freeze-dried powder injection according to claim 1 is characterized in that described other cosolvents are one or both in methyl parahydroxybenzoate, phenylalanine, the glutamic acid.
7. the described a kind of instant pirarubicin freeze-dried powder injection of claim 1 comprises each ingredients weight parts and is 10 parts of pirarubicin or NSC 654509,50～90 parts of lactose, 5～10 parts of nicotiamide.
8. the described a kind of instant pirarubicin freeze-dried powder injection of claim 7 comprises each ingredients weight parts and is 10 parts of pirarubicin or NSC 654509,80 parts of lactose, 10 parts of nicotiamide.
9. the preparation method of the described a kind of instant pirarubicin freeze-dried powder injection of claim 1, it is characterized in that pirarubicin or its pharmaceutically acceptable salt, cosolvent, excipient are dissolved in the water for injection, regulate pH value 3.5-6.5 with the PH regulator, 0.22 μ m microporous filter membrane aseptic filtration then, be sub-packed in the cillin bottle, lyophilization then, sterilization is towards nitrogen.
10. the preparation method of the described a kind of instant pirarubicin freeze-dried powder injection of claim 9, described pirarubicin pharmaceutically acceptable salt is the pirarubicin hydrochlorate, and cosolvent is a nicotiamide, and excipient is a lactose.
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| CN200910110676A CN101695479A (en) | 2009-10-21 | 2009-10-21 | Instant pirarubicin freeze-dried powder injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102949350A (en) * | 2011-08-16 | 2013-03-06 | 上海汇伦生命科技有限公司 | Lyophilized preparation of temozolomide and its preparation method |
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2009
- 2009-10-21 CN CN200910110676A patent/CN101695479A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102949350A (en) * | 2011-08-16 | 2013-03-06 | 上海汇伦生命科技有限公司 | Lyophilized preparation of temozolomide and its preparation method |
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Open date: 20100421 |