CN104203252A - Composition for injection - Google Patents
Composition for injection Download PDFInfo
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- CN104203252A CN104203252A CN201380018749.2A CN201380018749A CN104203252A CN 104203252 A CN104203252 A CN 104203252A CN 201380018749 A CN201380018749 A CN 201380018749A CN 104203252 A CN104203252 A CN 104203252A
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- Prior art keywords
- pirarubicin
- hydrochlorate
- maltose
- injection
- weight ratio
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed is a composition for an injection. The composition comprises pirarubicin that acts as an active medicinal agent and an additive, wherein pirarubicin has a form of pirarubicin hydrochloride and the additive is maltose and/or white soft sugar.
Description
Technical field
The present invention relates to the injection compositions that anthracene nucleus (anthracycline) is carcinostatic, more specifically, relate to the compositions of having improved as the deliquescent injection of the pirarubicin of this carcinostatic for providing.
Background technology
The pirarubicin preparation (excipient: lactose) of selling is at present that anthracene nucleus is the injection of carcinostatic, bad with respect to the dissolubility of normal saline.Therefore, carried out administration after being dissolved in distilled water for injection, but compared with normal saline, there is pain, to the strong so disadvantageous aspect of the stimulation of bladder.In order to improve this disadvantageous aspect, attempt improving the deliquescent effort (with reference to patent documentation 1, patent documentation 2) in normal saline.Particularly, the former has proposed: in order to improve the dissolubility of preparation, in the time of the manufacture of preparation, in the aqueous solution of the salt of active agents, add water-miscible organic solvent, then carry out lyophilization; The latter has proposed to use that to be considered to not exist with anthracene nucleus be that the antibiotic incompatible nicotiamide of anti-malignant tumor, Pyrazinamide or Radix Gentianae amide are as solubilizing agent.
Prior art document
Patent documentation
Patent documentation 1: No. 2915252 communique of Japan Patent
Patent documentation 2: No. 4456177 communique of Japan Patent.
Summary of the invention
Invent problem to be solved
According to prior art, improve that to contain anthracene nucleus be that the object of the such regulation of the dissolubility of the antibiotic injection of anti-malignant tumor is reached.But, according to patent documentation 2, illustrated that patent documentation 1(is equivalent to Japanese kokai publication hei No. 7-76515) in record invention due to operation problem thereby in fail implement state.On the other hand, in the invention of patent documentation 2, be the antibiotic incompatibility of anti-malignant tumor although do not exist with anthracene nucleus, use the compound all with certain physiologically active as solubilizing agent.If can realize desired object in the case of not using such compound, just can't be better.Therefore, the object of the present invention is to provide a kind of injection, wherein, is in carcinostatic especially in the injection with respect to the poorly soluble pirarubicin of normal saline containing anthracene nucleus, do not use the compound of specific demonstration physiologically active, improved the dissolubility of pirarubicin.
For solving the means of problem
The inventor etc. have here found now, while coordinating in the art conventionally many maltose using as excipient or white sugar with respect to pirarubicin hydrochlorate so that certain proportion is above, the dissolubility of the compositions of preparation in normal saline improves suddenly like this.About maltose or white sugar, in patent documentation 1 and 2, even also all disclose or hint as the use of excipient, therefore, above-mentioned experience is beyond the consideration.
Therefore, as the means that solve above-mentioned problem, a kind of injection compositions is provided, described injection compositions is the injection compositions containing as pirarubicin and the additive of active agents, pirarubicin hydrochlorate as the pirarubicin of active agents, additive is any a kind or 2 kinds that is selected from maltose and white sugar, and said composition is characterised in that, meet following a) ~ c) arbitrary condition.
A) weight ratio of pirarubicin hydrochlorate and maltose is 1: at least 22.
B) weight ratio of pirarubicin hydrochlorate and white sugar is 1: at least 22.
C) weight ratio of the total of pirarubicin hydrochlorate and white sugar and maltose is 1: at least 22.
Such compositions was dissolved in normal saline at 25 DEG C in 30 seconds, and the bin stability of lyophilization product with contain at present just not a halfpenny the worse compared with the injection lyophilization product of the pirarubicin of clinical use as excipient of lactose.
The detailed description of invention
Below, describe the present invention in detail.
For injection with for said injection in compositions, as long as being injected into the preparation in patient's body, be not subject to any restriction of its route of administration, medicine-feeding part, administering mode etc., but the special preparation of considering to intravenous, intra-arterial, intravesical administration.
For compositions, use with conventional in the art implication, refer to the mixture of material of more than two kinds.Therefore, in compositions, except above-mentioned active agents and additive, as long as according to object of the present invention, also can comprise conventional in the art other excipient, buffer agent or pH adjusting agent, osmotic pressure regulator, antiseptic, antioxidant etc.
Pirarubicin or pirarubicin hydrochlorate can be by the method preparations of recording in Japanese kokai publication sho 54-30146 communique, Japanese kokai publication sho 60-16998 communique, Japanese kokai publication sho 62-116591 communique or Japanese kokai publication hei 1-19091 communique.
Hydrophobicity as the pirarubicin hydrochlorate of the essential composition in the present invention is high, therefore, in the time wanting use lactose in the past as additive or excipient and the preparation prepared are dissolved in normal saline, even if use a large amount of lactose, also usually there is the situation of former medicine generation solubilizing poorly.But, although without being limited by theory, but can be understood as, if for example use maltose as excipient, eliminated the hydrophobicity of former medicine by maltose, therefore, for example, while adding 22 portions of above maltose with respect to 1 part of former medicine, there is theatrical variation in dissolubility, also can successfully dissolve even if former medicine becomes in normal saline.In addition, white sugar has also shown the behavior same with maltose.Therefore,, as long as comprise pirarubicin hydrochlorate and maltose or white sugar as additive using above-mentioned weight ratio, the content of additive does not have the upper limit in theory.But, consider that such compositions is provided with cryodesiccated form conventionally, in order to bring into play following 1) and 2) effect, preferably make the concentration of additive be not more than 135mg/mL.
1) can successfully implement lyophilization processing.
2) process the rear lyophilization piece obtaining and can not be formed on formation 2 layers or the thin outward appearance in bottom in bottle (vial).
Therefore, although unrestricted, but as the preferred mode of compositions of the present invention, can enumerate a kind of compositions, it is the injection compositions containing as pirarubicin and the additive of active agents, it is characterized in that, pirarubicin hydrochlorate as the pirarubicin of active agents, additive is any a kind or 2 kinds that is selected from maltose and white sugar, and, meet following a) ~ arbitrary condition in c).
A) weight ratio of pirarubicin hydrochlorate and maltose is 1:22～41.
B) weight ratio that pirarubicin hydrochlorate and white sugar are 1:22～41.
C) weight ratio of the total of pirarubicin hydrochlorate and white sugar and maltose is 1:22～41.
And then, as preferred mode, a) in, the weight ratio of pirarubicin hydrochlorate and maltose is 1:25～38, b) in, the weight ratio of pirarubicin hydrochlorate and white sugar is 1:25～38, c), in, the weight ratio of the total of pirarubicin hydrochlorate and maltose and white sugar is 1:25～38.
These compositions can be by preparing the powder of the powder of above-mentioned active agents and additive (especially any a kind or 2 kinds in Pharmacopeia of Japan maltose or Pharmacopeia of Japan white sugar (sucrose)) mechanical mixture.But, consider usually used as the prestige of injection use age and dissolve and use, after can be in respectively active agents and additive being dissolved in to water individually, both are mixed, or make to add the opposing party's solid matter and dissolve the solution lyophilization forming in the aqueous solution of one party and prepare.Above dissolution process can for example, be carried out under 0 DEG C～room temperature (, 20 DEG C～30 DEG C).
Lyophilization can be by being under reduced pressure dried to implement after medicinal liquid being cooled to-40 DEG C～-80 DEG C make it completely freezing.
For the compositions obtaining like this, with the form preparation of the compositions that contains active agents 10mg, the piece after lyophilization is vibrated at 25 DEG C be dissolved in 10mL normal saline (for example, Pharmacopeia of Japan normal saline) in time, dissolving in 30 seconds, and piece after lyophilization presents uniform outward appearance, do not present the outward appearance just as partial compression is bonding or form 2 layers or the thin outward appearance in bottom.And then, under the harsh storage environment that such lyophilization product is placed on to 40 DEG C, 60 DEG C time, show the bin stability with the active agents that has used the preparation of lactose to be equal to mutually.In this description, " dissolving " refers to, vibration certain hour carries out visualization when standing, and content dissolves completely.
On the other hand, for the freeze-dried product obtain for being just used as now the lactose of using at the excipient of the injection preparation of commercially available pirarubicin to replace above-mentioned additive to be prepared, the weight ratio of pirarubicin hydrochlorate and lactose being 1:15～31, in the time that dissolution velocity is the fastest, can by until the time shorten dissolving to approximately 1 minute, but compared with maltose, white sugar, need many especially lactose.In addition, use in the time that the D-mannital that is commonly used in the art excipient, D-Sorbitol, glucose, fructose replace above-mentioned additive, for D-mannital, D-Sorbitol, although improve to a certain extent the dissolubility of active agents, but bin stability is poor, in addition, for glucose, fructose, the preparation of freeze-dried product itself is difficult.
Can by composition dissolves of the present invention at normal saline (for example pass through, Pharmacopeia of Japan normal saline) in liquid and make injection, but also (for example can be dissolved in water for injection, Pharmacopeia of Japan water for injection) or 5% glucose injection (for example, Pharmacopeia of Japan glucose injection) in and make injection.
Embodiment
Below, enumerate object lesson and further specifically describe the present invention, but be not intended to limit the invention to these examples.
Example 1: the Production Example of pirarubicin preparation
Use raw material
About pirarubicin hydrochlorate (also referred to as THP), prepare to adding hydrochloric acid in pirarubicin (Japanese マ イ Network ロ バ イ オ フ ァ ー マ company system).
About maltose, white sugar and lactose, be directly used as respectively the commercially available product of Pharmacopeia of Japan product.
About trehalose, directly use (strain) woods protobiochemistry institute system trehalose.
1-1: the method for making of amount of liquid medicine (also referred to as medicinal liquid loading) the 3mL preparation when lyophilization of lactose 250mg THP10mg titre
By pirarubicin hydrochlorate 100mg(titre) and lactose 2.5g be dissolved in water, be adjusted to pH6 with sodium hydroxide, after making total amount be 30mL, carry out aseptic filtration, be encased in the amount of each bottle 3mL in the vial of 15mL capacity, after filling, carry out lyophilization, obtained freeze-dried product.
1-2: the method for making of maltose 290mg THP10mg titre medicinal liquid loading 3mL preparation
By pirarubicin hydrochlorate 840mg(titre) and maltose 24.4g be dissolved in water, be adjusted to pH6 with sodium hydroxide, after making total amount be 252mL, carry out aseptic filtration, be encased in the amount of each bottle 3mL in the vial of 15mL capacity, after filling, carry out lyophilization, obtained freeze-dried product.
1-3: the method for making of white sugar 250mg THP10mg titre medicinal liquid loading 3mL preparation
By pirarubicin hydrochlorate 100mg(titre) and white sugar 2.5g be dissolved in water, be adjusted to pH6 with sodium hydroxide, after making total amount be 30mL, carry out aseptic filtration, be encased in the amount of each bottle 3mL in the vial of 15mL capacity, after filling, carry out lyophilization, obtained freeze-dried product.
1-4: the method for making of maltose 250mg THP10mg titre medicinal liquid loading 2mL preparation
By pirarubicin hydrochlorate 100mg(titre) and maltose 2.5g be dissolved in water, be adjusted to pH6 with sodium hydroxide, after making total amount be 20mL, carry out aseptic filtration, be encased in the amount of each bottle 2mL in the vial of 15mL capacity, after filling, carry out lyophilization, obtained freeze-dried product.
1-5: the method for making of trehalose 250mg THP10mg titre medicinal liquid loading 3mL preparation
By pirarubicin hydrochlorate 100mg(titre) and trehalose 2.5g be dissolved in water, be adjusted to pH6 with sodium hydroxide, after making total amount be 30mL, carry out aseptic filtration, be encased in the amount of each bottle 3mL in the vial of 15mL capacity, after filling, carry out lyophilization, obtained freeze-dried product.
1-6: the method for making of the THP10mg titre medicinal liquid loading 3mL preparation of the mixture that comprises maltose and white sugar
By pirarubicin hydrochlorate 100mg(titre) and maltose and white sugar be dissolved in water, be adjusted to pH6 with sodium hydroxide, after making total amount be 30mL, carry out aseptic filtration, be encased in the amount of each bottle 3mL in the vial of 15mL capacity, after filling, carry out lyophilization, obtained freeze-dried product.
Example 2: the solubility test of freeze-dried product in normal saline
In the freeze-dried product obtaining to operating as example 1, add normal saline 10mL and vibrate, measuring until the time completely of the solid matter in bottle.The results are shown in following table 1～5.The kind of the additive comprising with respect to the pirarubicin hydrochlorate 10mg that forms freeze-dried product and amount are used with the amount shown in table respectively.
[table 1]
[table 2]
[table 3]
[table 4]
[table 5]
The trial target of preparing under each condition of above-mentioned table 1～table 5 has obtained freeze-dried product all no problemly.
Example 3: the stability test under critical conditions of freeze-dried product
Under the environment of 60 DEG C and 40 DEG C, the injection (containing maltose 270mg) that keeping is manufactured in the freeze-dried product of the record manufacture according to example 1, has measured the residual rate of the pirarubicin between the maintaining period shown in table.It should be noted that, product in contrast, the preparation product in the past that uses every THP10mg to contain lactose 90mg has similarly been measured residual rate.Show the result in table 6.
[table 6]
Industrial usability
The injection compositions containing as pirarubicin and the additive of active agents of the present invention, in the time preparing injection, can make active agents promptly be dissolved in normal saline, and bin stability excellence, thereby can be applicable to the pharmaceutical industries of pirarubicin preparation.
Claims (7)
1. a compositions, it is the injection compositions containing as pirarubicin and the additive of active agents, it is characterized in that,
Be pirarubicin hydrochlorate as the pirarubicin of active agents, additive is a kind or 2 kinds that is selected from maltose and white sugar, and, described compositions meet following a) ~ arbitrary condition in condition c),
A) weight ratio of pirarubicin hydrochlorate and maltose is 1: at least 22,
B) weight ratio of pirarubicin hydrochlorate and white sugar is 1: at least 22,
C) weight ratio of the total of pirarubicin hydrochlorate and white sugar and maltose is 1: at least 22.
2. injection compositions according to claim 1, and, it is characterized in that, meet following a) ~ arbitrary condition in condition c),
A) weight ratio of pirarubicin hydrochlorate and maltose is 1:22～41,
B) weight ratio of pirarubicin hydrochlorate and white sugar is 1:22～41,
C) weight ratio of the total of pirarubicin hydrochlorate and white sugar and maltose is 1:22～41.
3. compositions according to claim 1, wherein, the weight ratio of pirarubicin hydrochlorate and maltose is 1:22～41.
4. compositions according to claim 1, wherein, the weight ratio of pirarubicin hydrochlorate and white sugar is 1:22～41.
5. compositions according to claim 1, it is the form of lyophilization product.
6. compositions according to claim 1, it is the form of lyophilization product, and, when contain 10mg pirarubicin hydrochlorate time, at 25 DEG C, in 30 seconds, be dissolved in the normal saline of 10mL.
7. according to the compositions described in any one in claim 1～6, wherein, pirarubicin hydrochlorate is the dosage form that comprises 10mg or 20mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810134451.2A CN108159005B (en) | 2012-04-09 | 2013-04-05 | Composition for injection |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012088678 | 2012-04-09 | ||
| JP2012-088678 | 2012-04-09 | ||
| PCT/JP2013/060466 WO2013154045A1 (en) | 2012-04-09 | 2013-04-05 | Composition for injectable solution |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810134451.2A Division CN108159005B (en) | 2012-04-09 | 2013-04-05 | Composition for injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104203252A true CN104203252A (en) | 2014-12-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380018749.2A Pending CN104203252A (en) | 2012-04-09 | 2013-04-05 | Composition for injection |
| CN201810134451.2A Active CN108159005B (en) | 2012-04-09 | 2013-04-05 | Composition for injection |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201810134451.2A Active CN108159005B (en) | 2012-04-09 | 2013-04-05 | Composition for injection |
Country Status (3)
| Country | Link |
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| JP (1) | JP6204349B2 (en) |
| CN (2) | CN104203252A (en) |
| WO (1) | WO2013154045A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20230173027A1 (en) | 2020-04-20 | 2023-06-08 | Shionogi & Co., Ltd. | Formulation containing hmgb1 partial peptide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167698A (en) * | 2007-12-06 | 2008-04-30 | 张文芳 | Freezing-dried preparation containing pirarubicin |
| CN101190188A (en) * | 2006-11-30 | 2008-06-04 | 北京天衡药物研究院 | Anthracene nucleus medicinal liposome injection and preparation method |
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| JPS5982395A (en) * | 1982-11-02 | 1984-05-12 | Microbial Chem Res Found | Anthracycline compound, its preparation and use |
| JPH0742232B2 (en) * | 1989-03-02 | 1995-05-10 | 明治製菓株式会社 | Anticancer composition |
| JPH0776515B2 (en) * | 1990-02-16 | 1995-08-16 | 日本鋼管工事株式社社 | Civil engineering method for underground pipes |
| JP2915252B2 (en) * | 1993-06-30 | 1999-07-05 | 明治製菓株式会社 | Method for producing a formulation with improved solubility |
| AU5246900A (en) * | 1999-06-14 | 2001-01-02 | Japan Science And Technology Corporation | Anticancer emulsions containing anthracycline compounds |
| JP2004010479A (en) * | 2002-06-03 | 2004-01-15 | Japan Science & Technology Corp | New solid pharmaceutical preparation comprising block copolymer and anthracycline anticancer agent, and method for producing the same |
| AU2008250518B2 (en) * | 2007-05-16 | 2013-09-12 | Ktb Tumorforschungsgesellschaft Mbh | Low-viscous anthracycline formulation |
| CN101795694B (en) * | 2007-09-04 | 2012-10-10 | 明治制果药业株式会社 | Injection, injection solution and injection kit preparation |
| CN101181280B (en) * | 2007-11-23 | 2010-07-14 | 深圳万乐药业有限公司 | Pirarubicin freeze-dry preparations and preparation method thereof |
| CN101234205B (en) * | 2008-02-28 | 2011-01-19 | 中国科学院长春应用化学研究所 | High molecule adriamycin bonding medicine nano capsule with targeting function and preparation thereof |
| CN101234204B (en) * | 2008-02-28 | 2010-09-29 | 中国科学院长春应用化学研究所 | High molecule bonding adriamycin medicine, nano capsule and preparation thereof |
| CN101361747A (en) * | 2008-08-11 | 2009-02-11 | 张文芳 | Adriablastina freeze-drying preparation with stable albumin and use thereof in treating tumor |
| CN101361746A (en) * | 2008-08-11 | 2009-02-11 | 张文芳 | Stable adriablastina albumin lipid drug-loading system and preparation method thereof |
| CN101670112A (en) * | 2008-08-11 | 2010-03-17 | 苏州世林医药技术发展有限公司 | Stable albumins lipid medicine carrying system and preparation method thereof |
-
2013
- 2013-04-05 WO PCT/JP2013/060466 patent/WO2013154045A1/en active Application Filing
- 2013-04-05 CN CN201380018749.2A patent/CN104203252A/en active Pending
- 2013-04-05 JP JP2014510147A patent/JP6204349B2/en active Active
- 2013-04-05 CN CN201810134451.2A patent/CN108159005B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101190188A (en) * | 2006-11-30 | 2008-06-04 | 北京天衡药物研究院 | Anthracene nucleus medicinal liposome injection and preparation method |
| CN101167698A (en) * | 2007-12-06 | 2008-04-30 | 张文芳 | Freezing-dried preparation containing pirarubicin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108159005B (en) | 2021-03-23 |
| JP6204349B2 (en) | 2017-09-27 |
| CN108159005A (en) | 2018-06-15 |
| WO2013154045A1 (en) | 2013-10-17 |
| JPWO2013154045A1 (en) | 2015-12-17 |
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Application publication date: 20141210 |