WO2007142440A1 - Stable pharmaceutical composition containing paclitaxel and a method of manufacturing the same - Google Patents
Stable pharmaceutical composition containing paclitaxel and a method of manufacturing the same Download PDFInfo
- Publication number
- WO2007142440A1 WO2007142440A1 PCT/KR2007/002694 KR2007002694W WO2007142440A1 WO 2007142440 A1 WO2007142440 A1 WO 2007142440A1 KR 2007002694 W KR2007002694 W KR 2007002694W WO 2007142440 A1 WO2007142440 A1 WO 2007142440A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- paclitaxel
- cyclodextrin
- composition
- polyvinylpyrrolidone
- composition according
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- the present invention relates to a stable injection composition
- a stable injection composition comprising
- paclitaxel and a method of preparing the same, more particularly to an injection
- composition comprising paclitaxel with improved storage stability compared with
- PVP polyvinylpyrrolidone
- freeze-drying and a method of preparing the same.
- Paclitaxel is well known as 'Taxol'. It has substantial in vivo activity against
- paclitaxel requires addition of a surfactant and ethanol to improve its solubility, and ethanol is known as the best solvent to solubilize paclitaxel.
- stock solution containing
- Taxol in a solvent mixture composed of ethanol and Cremophor
- infusion solution to about 0.03 to 0.6 mg/mL.
- WO 98/30205 discloses a method of using PEGylated vitamin E as a
- Korean Patent No. 310839 discloses a method of preparing a
- polyoxyethylene glycerol ricinoleate polysorbate 80, anhydrous ethanol
- alcohol intoxication or hypersensitive reaction e.g., anhydrous ethanol
- WO 99/24073 discloses a method to increase the solubility of paclitaxel
- paclitaxel is dissolved in a small amount of ethanol and the resultant solution is
- cyclodextrin is in the range of from 1:25 to 1:400 based on its weight. It also
- composition in 5% dextrose solution has a concentration of 0.3-1.2 mg/mL and
- coprecipitation compound may precipitate if the concentration of the active
- the present inventors completed the present invention by preparing an
- injection composition comprising paclitaxel with improved solubility and stability
- PVP polyvinylpyrrolidone
- an object of the present invention is to provide a stable injection
- composition comprising paclitaxel and a method of preparing the same.
- the present invention relates to a stable injection composition
- a stable injection composition comprising
- paclitaxel prepared from a liquid composition comprising paclitaxel, cyclodextrin
- PVP polyvinylpyrrolidone
- the present invention also relates to a method of preparing a stable injection composition comprising paclitaxel, which comprises the steps of:
- Paclitaxel is reacted in distilled water in the presence of
- PVP polyvinylpyrrolidone
- step V paclitaxel, and cyclodextrin and polyvinylpyrrolidone (PVP),
- Paclitaxel used in the present invention may be in either a free form or a salt
- cyclodextrins have hydrophobic cavities of a uniform size
- cyclodextrins are classified into ⁇ -cyclodextrin, ⁇ -cyclodextrin
- any other cyclodextrin derivatives may be used in the
- ⁇ -cyclodextrins having a cavity diameter in the
- cyclodextrin is used in the amount of
- MS degree of molecular substitution
- the composition may become too viscous making the
- a water-soluble polymer is used in the present invention to improve
- polyethylene glycol solubility and stability in the reaction solution.
- polyethylene glycol polyethylene glycol
- PEG polyvinylpyrrolidone
- CMC carboxymethyl cellulose
- HPC hydroxymethyl cellulose
- HMC hydroxymethyl cellulose
- HEC hydroxyethyl cellulose
- HPMC hydroxypropylmethyl cellulose
- HPEC hydroxypropylethyl cellulose
- polyvinylpyrrolidone PVP
- polyvinylpyrrolidone one having a K-value in the range of from 10 to 20 is
- the water-soluble polymer is comprised preferably in the amount of 0.1-100
- the water-soluble polymer is comprised in less than 0.1
- the solution used in the present invention may be any one that can be used as
- a perfusion fluid preferably distilled water.
- step 2) the mixture solution is heated and stirred for stabilization and
- the mixture solution is frozen
- resultant composition has white to yellow color.
- step 3 the composition is diluted.
- the diluent may be any solution that
- dilution can vary greatly
- the resultant stock solution has
- a paclitaxel with a concentration of 1-10.0 mg/mL, more preferably 4-8 mg/mL.
- the injection composition is not harmful to human body.
- a white composition was prepared in the same manner as in Example 1,
- Examples 1 to 3 showed superior storage stability than to of Comparative Example 1.
Abstract
The present invention relates to a stable injection composition comprising paclitaxel and a method of preparing the same. More particularly, the present invention relates to an injection composition comprising paclitaxel with improved storage stability compared with conventional injection compositions, prepared by dissolving paclitaxel, a water-insoluble compound, in distilled water after mixing it with cyclodextrin and polyvinylpyrrolidone (PVP) in order to stabilize paclitaxel, followed by freeze-drying, and a method of preparing the same.
Description
[DESCRIPTION]
[Title]
STABLE PHARMACEUTICAL COMPOSITION CONTAINING
PACLITAXEL AND A METHOD OF MANUFACTURING THE SAME
[Technical Field]
The present invention relates to a stable injection composition comprising
paclitaxel and a method of preparing the same, more particularly to an injection
composition comprising paclitaxel with improved storage stability compared with
conventional injection compositions, prepared by dissolving paclitaxel, a
water-insoluble compound, in distilled water after mixing it with cyclodextrin and
polyvinylpyrrolidone (PVP) in order to stabilize paclitaxel, followed by
freeze-drying, and a method of preparing the same.
[Background Art]
Paclitaxel is well known as 'Taxol'. It has substantial in vivo activity against
malignant tumors thus being effective in treating non-small cell lung cancer, ovarian
cancer, breast cancer and the like.
Due to poor water solubility of paclitaxel, however, an injection solution
comprising paclitaxel requires addition of a surfactant and ethanol to improve its
solubility, and ethanol is known as the best solvent to solubilize paclitaxel.
As an example, in the publication by Rowinsky, Lorraine Cazenave and
Donehower (Journal of the National Cancer Institute, vol. 82, No. 15, p.1247-1529 on
Aug. 1, 1990), there is prepared a first solution, termed "stock solution", containing
about 6 mg/mL of Taxol in a solvent mixture composed of ethanol and Cremophor
EL. To prepare it as an injection, this solution is mixed with an infusion fluid
containing dextrose or physiological saline. To obtain a mixture which is stable
from both physical and chemical points of view, the authors of the above publication
asserted that it is necessary to limit the concentration of active ingredient in the
infusion solution to about 0.03 to 0.6 mg/mL.
In general, it is known more effective in treating cancers to inject a sufficient
amount of active ingredient. Therefore, clinicians prefer to inject an active
ingredient with a concentration in the range of from about 0.3 to about 1 mg/mL in
the fluid. If the dosage is higher than the above, there would occur an anaphylactic
shock, a phenomenon hard to control, mainly due to the Cremophor. The
publication also discloses that, to obtain such concentration, it is necessary to inject a
solution, in addition to the active ingredient, containing a high concentration of
ethanol, which may cause alcohol intoxication.
WO 98/30205 discloses a method of using PEGylated vitamin E as a
surfactant (E) and US 2004/0127551 discloses a method of using vitamin E TPGS
(D-α-tocopheryl polyethylene glycol 1000 succinate). But, they failed to prepare a
stable composition comprising a high concentration of the active ingredient.
Korean Patent No. 310839 discloses a method of preparing a
polyvinylpyrrolidone matrix and mixing it with anhydrous ethanol and such solvent
as polyoxyethylene glycerol ricinoleate, polysorbate 80, anhydrous ethanol,
polyethylene glycol, and so forth to obtain an injection.
However, this invention is also disadvantageous in that the substances that
may cause alcohol intoxication or hypersensitive reaction (e.g., anhydrous ethanol
and polysorbate 80).
WO 99/24073 (1997) discloses a method to increase the solubility of paclitaxel
in water by using cyclodextrin rather than a surfactant. More particularly,
paclitaxel is dissolved in a small amount of ethanol and the resultant solution is
added to 5 % dextrose solution of acetyl-γ-cyclodextrin (Ac-γ-CD) or
hydroxypropylmethyl-β-cyclodextrin (HP-β-CD). Then, ethanol is removed as
much as possible by evaporation or other adequate means and freeze-drying is
performed to obtain a wanted composition. A suitable rate of an active ingredient
to cyclodextrin is in the range of from 1:25 to 1:400 based on its weight. It also
discloses that an infusion fluid obtained by further diluting the resultant
composition in 5% dextrose solution has a concentration of 0.3-1.2 mg/mL and
maintains physical stability for over 72 hours.
However, this invention has a drawback that the diluted solution of the
coprecipitation compound may precipitate if the concentration of the active
ingredient is low or physical stability may decrease when the coprecipitation
compound is dissolved or diluted for use.
[Disclosure of the Invention]
The present inventors completed the present invention by preparing an
injection composition comprising paclitaxel with improved solubility and stability
than conventional injection preparations by mixing water-insoluble paclitaxel with
hydroxy propyl-β-cyclodextrin and a water-soluble polymer such as
polyvinylpyrrolidone (PVP) in distilled water, in order to stabilize paclitaxel, and
freeze-drying the mixture.
Accordingly, an object of the present invention is to provide a stable injection
composition comprising paclitaxel and a method of preparing the same.
[Best Mode for Carrying Out the Invention]
The present invention relates to a stable injection composition comprising
paclitaxel prepared from a liquid composition comprising paclitaxel, cyclodextrin
and polyvinylpyrrolidone (PVP).
The present invention also relates to a method of preparing a stable injection
composition comprising paclitaxel, which comprises the steps of:
1) mixing paclitaxel, cyclodextrin and polyvinylpyrrolidone (PVP), which are
water-soluble polymers, in distilled water;
2) freeze-drying the mixture to obtain a freeze-drying composition; and
3) diluting the freeze-drying composition in a dextrose solution or
physiological saline to obtain a liquid composition.
Hereunder is given a detailed description of the present invention.
The present invention is characterized in stabilizing paclitaxel with
cyclodextrin. Paclitaxel is reacted in distilled water in the presence of
polyvinylpyrrolidone (PVP), which is a water-soluble polymer. As a result, a
high-concentration stock solution for injection is obtained, without using additives
that may induce side reactions such as ethanol and polysorbate.
The process of preparing an injection composition comprising paclitaxel in
accordance with the present invention is described in detail.
In step V), paclitaxel, and cyclodextrin and polyvinylpyrrolidone (PVP),
which are water-soluble polymers, are mixed in distilled water.
Paclitaxel used in the present invention may be in either a free form or a salt
thereof.
Structurally, cyclodextrins have hydrophobic cavities of a uniform size and
protect hydrophobic compounds from external environment by lodging them in the
cavities. Typically, cyclodextrins are classified into α-cyclodextrin, β-cyclodextrin
and γ-cyclodextrin depending on the property and size. Apart from the
afore-mentioned three kinds, any other cyclodextrin derivatives may be used in the
present invention. Preferably, β-cyclodextrins having a cavity diameter in the
range of from 6.0 to 6.5 A or derivatives thereof are used, more preferably
hydroxypropyl-β-cyclodextrin. Preferably, cyclodextrin is used in the amount of
5-400 parts by weight, more preferably in the amount of 50-200 parts by weight, per
1 part by weight of paclitaxel. If excessive cyclodextrin is used, the stock solution
will become too viscous. In contrast, if cyclodextrin is used too little, a wanted
stability may not be attained. For the hydroxypropyl-β-cyclodextrin, one having a
degree of molecular substitution (MS) of 0.2-1.0, preferably 0.4-0.8, is suitable. If
the degree of molecular substitution is too low, solubility may not be good. In
contrast, if it is too high, the composition may become too viscous making the
handling process difficult.
Further, a water-soluble polymer is used in the present invention to improve
solubility and stability in the reaction solution. For example, polyethylene glycol
(PEG), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxypropyl
cellulose (HPC), hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC),
hydroxypropylmethyl cellulose (HPMC), hydroxypropylethyl cellulose (HPEC), etc.,
may be used. Preferably, polyvinylpyrrolidone (PVP) , is used. As for
polyvinylpyrrolidone, one having a K-value in the range of from 10 to 20 is
preferable. If the K-value of polyvinylpyrrolidone is smaller than 10, solubility and
stability decrease significantly and, if it is higher than 20, handling and development
into an injection become difficult due to high viscosity.
The water-soluble polymer is comprised preferably in the amount of 0.1-100
parts by weight, more preferably in the amount of 1.0-5.0 parts by weight, per 1 part
by weight of paclitaxel. If the water-soluble polymer is comprised in less than 0.1
part by weight, improvement of solubility and stability will become minimal. In
contrast, if it is used in excess of 100 parts by weight, the reaction solution becomes
too viscous, making filtering and washing impossible and lowering the solubility of
the composition.
The solution used in the present invention may be any one that can be used as
a perfusion fluid, preferably distilled water.
In step 2), the mixture solution is heated and stirred for stabilization and
freeze-dried to prepare a composition. The stirring is performed at a temperature
of 20-50 0C, preferably at 20-25 0C. For freeze drying, the mixture solution is frozen
at a low temperature and then the pressure is lowered at -50 to -60 0C. The
resultant composition has white to yellow color.
In step 3), the composition is diluted. The diluent may be any solution that
can be used in preparing injections. Preferably, 5-10 % dextrose solution or 0.9 %
physiological saline is suitable for the diluent. The dilution can vary greatly
depending on the preparation method. Preferably, the resultant stock solution has
a paclitaxel with a concentration of 1-10.0 mg/mL, more preferably 4-8 mg/mL.
Since the resultant stock solution of the composition has excellent storage
stability, it can be stored for a relatively long period of time, easily prepared into
injection and can tolerate temperature and humidity conditions of the production
process without being decomposed.
Further, due to absence of ethanol or other additives that may cause
hypersensitive reactions, the injection composition is not harmful to human body.
Practical and presently preferred embodiments of the present invention are
further illustrated as shown in the following examples; however, they should not be
construed as limiting the scope of the present invention.
Example 1
A mixture of 10 mg of paclitaxel, 30 mg of polyvinylpyrrolidone K-12 and 1.0
g hydroxypropyl-β-cyclodextrin (MS = 0.6) was dissolved in 5 mL of distilled water
and stirred homogeneously at room temperature. The solubility was 1.7 mg/mL.
Upon complete dissolution, the solution was filtered through 0.22 μm filter paper
and the filtrate was cooled to -80 °C and freeze-dried to obtain a composition. The
resultant composition was completely dissolved in 5 mL of 5 % dextrose solution to
prepare a stock solution.
Example 2
A mixture of 30 mg of paclitaxel, 90 mg of polyvinylpyrrolidone K-12 and 5.0
g hydroxypropyl-β-cyclodextrin (MS = 0.6) was dissolved in 5 mL of distilled water
and stirred homogeneously at room temperature. The solubility was 3.0 mg/mL.
Upon complete dissolution, the solution was filtered through 0.22 μm filter paper
and the filtrate was cooled to -80 °C and freeze-dried to obtain a composition. The
resultant composition was completely dissolved in 5 mL of 5 % dextrose solution to
prepare a stock solution.
Example 3
A mixture of 30 mg of paclitaxel, 90 mg of polyvinylpyrrolidone K-18 and 5.0
g hydroxypropyl-β-cyclodextrin (MS = 0.6) was dissolved in 5 mL of distilled water
and stirred homogeneously at room temperature. The solubility was 3.0 mg/mL.
Upon complete dissolution, the solution was filtered through 0.22 μm filter paper
and the filtrate was cooled to -80 0C and freeze-dried to obtain a composition. The
resultant composition was completely dissolved in 5 mL of 5 % dextrose solution to
prepare a stock solution.
Comparative Example 1
A white composition was prepared in the same manner as in Example 1,
except for not using polyvinylpyrrolidone.
Experimental Example 1: Storage stability test
Stability test was carried out at room temperature for the compositions
prepared in Examples 1 to 3 and Comparative Example 1. Concentration change
with time was measured by HPLC.
[Table 1]
As shown in Table 1, the compositions in accordance with the present
invention (Examples 1 to 3) showed superior storage stability than to of
Comparative Example 1.
As described in detail above, the paclitaxel-containing composition in
accordance with the present invention has excellent storage stability, and thus it can
be stored for a long period of time, easily prepared into injection and is capable of
tolerating temperature and humidity conditions of the production process without
being decomposed. Further, ethanol or polysorbate is not contained in the
composition, and thus there are few side reactions.
Although the preferred embodiments of the present invention have been
disclosed for illustrative purposes, those skilled in the art will appreciate that
various modifications, additions and substitutions are possible, without departing
from the scope and spirit of the present invention as disclosed in the accompanying
claims.
Claims
[Claim 1]
A stable injection composition comprising paclitaxel, cyclodextrin and
polyvinylpyrrolidone (PVP).
[Claim 2]
The composition according to Claim 1, wherein said the paclitaxel is a free
form or a derivative thereof.
[Claim 3]
The composition according to Claim 1, wherein said cyclodextrin is used in
the amount of 5-400 parts by weight per 1 part by weight of paclitaxel.
[Claim 4]
The composition according to Claim 1, wherein said polyvinylpyrrolidone is
added in the amount of 0.1-100 parts by weight per 1 part by weight of paclitaxel.
[Claim 5]
The composition according to Claim 1, wherein said cyclodextrin is
β-cyclodextrin or a derivative thereof.
[Claim 6]
The composition according to Claim 1, wherein said cyclodextrin is
hydroxypropyl-β-cyclodextrin.
[Claim 7]
The composition according to Claim 6, wherein said
hydroxypropyl-β-cyclodextrin has a degree of molecular substitution (MS) of from
0.2 to 1.0.
[Claim 8]
The composition according to Claim 1, wherein said polyvinylpyrrolidone
has a K-value of from 10 to 20.
[Claim 9]
A method of preparing a stable injection composition comprising paclitaxel,
which comprises the steps of:
1) mixing paclitaxel, cyclodextrin and polyvinylpyrrolidone (PVP), which are
water-soluble polymers, in distilled water;
2) freeze-drying the mixture solution to prepare a freeze-drying composition; and
3) diluting the resultant composition in a dextrose solution or physiological
saline to prepare a liquid composition.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2006-0049833 | 2006-06-02 | ||
| KR20060049833 | 2006-06-02 | ||
| KR10-2007-0054058 | 2007-06-01 | ||
| KR1020070054058A KR100917810B1 (en) | 2006-06-02 | 2007-06-01 | Stable Pharmaceutical Composition containing Paclitaxel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007142440A1 true WO2007142440A1 (en) | 2007-12-13 |
Family
ID=38801652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2007/002694 WO2007142440A1 (en) | 2006-06-02 | 2007-06-04 | Stable pharmaceutical composition containing paclitaxel and a method of manufacturing the same |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2007142440A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2219616A2 (en) * | 2007-11-22 | 2010-08-25 | SK Chemicals, Co., Ltd. | Lyophilized pharmaceutical composition with improved stability containing taxane derivatives, and method of manufacturing the same |
| CN110279657A (en) * | 2019-07-29 | 2019-09-27 | 河南官渡生物工程有限公司 | A kind of sodium closantel injection and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999024073A1 (en) * | 1997-11-10 | 1999-05-20 | Thissen Laboratoires S.A. | Pharmaceutical compositions containing cyclodextrins and taxoids |
| KR20000061113A (en) * | 1999-03-23 | 2000-10-16 | 정기련 | An improved stable paclitaxel injection concentrate |
| US20050255164A1 (en) * | 2002-08-15 | 2005-11-17 | Yunging Liu | Solid nano pharmaceutical formulation and preparation method thereof |
-
2007
- 2007-06-04 WO PCT/KR2007/002694 patent/WO2007142440A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999024073A1 (en) * | 1997-11-10 | 1999-05-20 | Thissen Laboratoires S.A. | Pharmaceutical compositions containing cyclodextrins and taxoids |
| KR20000061113A (en) * | 1999-03-23 | 2000-10-16 | 정기련 | An improved stable paclitaxel injection concentrate |
| US20050255164A1 (en) * | 2002-08-15 | 2005-11-17 | Yunging Liu | Solid nano pharmaceutical formulation and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2219616A2 (en) * | 2007-11-22 | 2010-08-25 | SK Chemicals, Co., Ltd. | Lyophilized pharmaceutical composition with improved stability containing taxane derivatives, and method of manufacturing the same |
| EP2219616A4 (en) * | 2007-11-22 | 2014-05-14 | Sk Chemicals Co Ltd | Lyophilized pharmaceutical composition with improved stability containing taxane derivatives, and method of manufacturing the same |
| CN110279657A (en) * | 2019-07-29 | 2019-09-27 | 河南官渡生物工程有限公司 | A kind of sodium closantel injection and preparation method thereof |
| CN110279657B (en) * | 2019-07-29 | 2021-07-27 | 河南官渡生物工程有限公司 | Closantel sodium injection and preparation method thereof |
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