CN101087591B - Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it - Google Patents
Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it Download PDFInfo
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- CN101087591B CN101087591B CN200580044730.0A CN200580044730A CN101087591B CN 101087591 B CN101087591 B CN 101087591B CN 200580044730 A CN200580044730 A CN 200580044730A CN 101087591 B CN101087591 B CN 101087591B
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- solid dispersion
- dispersion
- stable solid
- polyethylene glycol
- vinorelbine
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- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
Abstract
This invention relates to solid and stable dispersions of a hydrosoluble derivative of vinca alkaloids in at least one polyethyleneglycol with a molecular mass between 800 and 30,000.
Description
The present invention relates to the soluble derivative of vinca alkaloids, the two stable solid dispersion of tartrate at least a Polyethylene Glycol of derivant, the particularly vinorelbine of vinorelbine more especially, it is used for mixing the pharmaceutical composition of Orally administered this Herba Catharanthi Rosei derivant.
The antitumor chemotherapy of initial exploitation is used the intravenous method.Support the reason of this application process to have: than oral methods
-still less gastrointestinal toxicity,
-total bioavailability and
Expose difference between-potential lower patient or in the patient.
But the intravenous method is with the major defect that limits its use: the pathogenicity rate of vein treatment (vein access), the possible complication of maincenter venous access (infect, thrombosis), the risk of exosmosing.
Since may be for the patient out and out benefit, the chemotherapeutic oral form several years of antitumor have constantly obtained exploitation.In addition, become when the selecting therapeutic strategy pharmacoeconomics factor that becomes more and more important also causes the exploitation of oral medication.
For new synthesis of derivatives (for example UFT, Ka Peitabin, S-I), platinum derivatives (for example JM-216) or the vinca alkaloids (for example vinorelbine) of previous active component (for example etoposide, cyclophosphamide and darubicin), fluorine pyridines, numerous exploration work have been carried out for the possible purposes of the molecule that is used for the treatment of cancer and dosage forms for oral administration.
Therefore, the invention still further relates to the stable pharmaceutical composition of vinca alkaloids, particularly vinorelbine for Orally administered discrete form.
Vinorelbine or 3 ', 4 '-dihydro-4 '-deoxidation-8 '-NVB is the alcaloid-derivatives of Herba Catharanthi Rosei, it brings into play cyto-inhibition by suppressing microtubule polymerization.
Vinorelbine, more especially the salt of vinorelbine is that the two tartrates of vinorelbine also have activity in treatment maxicell pulmonary carcinoma and breast carcinoma.Injection form was gone on the market in France first in 1989.It is being sold to desire to be diluted the solution form that is used for perfusion now all over the world, and described solution is diluted to the concentration in alkaline vinorelbine 10mg/ml, and is sub-packed in the bottle, and unit volume is 1ml and 5ml.
In recent years, developed the solution oral formulations of vinorelbine and with NAVELBINE Oral
The title of soft capsule is put on market.Said preparation is the Perle form that contains the two tartrates of vinorelbine and excipient mixture, and described excipient mixture comprises Polyethylene Glycol, glycerol, second alcohol and water.The mean molecule quantity of Polyethylene Glycol is 200 to 600: these are liquid macrogol such as MACROGOL 400.The unit dose of representing with alkaline vinorelbine is 5mg to 100mg, more advantageously equals 20mg, 30mg, 40mg and 80mg.
These soft capsules are addressed among the patent application WO03/101383 of Inc. at R.P.Scherer Technologies.
The vinca alkaloids derivant, the particularly vinorelbine that are used for Orally administered discrete form according to pharmaceutical composition of the present invention.They contain the soluble derivative that is dispersed in the vinca alkaloids in semisolid or the solid polyethylene glycol, advantageously vinorelbine salt, be more particularly two tartrates.
More accurately, stable solid dispersion according to the present invention is united the soluble derivative that vinca alkaloids is arranged, and it is in especially, and at least a molecular weight is 800 to 30000 Polyethylene Glycol, more especially molecular weight is in 1000 to 6000 the Polyethylene Glycol.
The mean molecule quantity of the selected Polyethylene Glycol of the present invention is greater than about 800.When molecular weight was 800 to 2000, they were semi-solid form, and when molecular weight was higher, they were solid form.They are distinguished from each other by its fusing point, and are as shown in the table.
| Polyethylene Glycol (mean molecule quantity) | 1000 | ?1500 | ?4000 | ?6000 | ?8000 | ?20000 | ?30000 |
| Fusing point | 37 ℃ to 40 ℃ | 44 ℃ to 48 ℃ | 50 ℃ to 58 ℃ | 55 ℃ to 63 |
60 ℃ to 63 |
60 ℃ to 63 ℃ | 65 ℃ to 70 ℃ |
A kind of advantageous embodiment according to the present invention, the soluble derivative of vinca alkaloids, more special at first be that the mass ratio of the two tartrates of vinorelbine and the Polyethylene Glycol of next is 1.5: 1 to 1: 10, preferred 1: 3 to 1: 6.
Salt these dispersions in Polyethylene Glycol according to vinca alkaloids derivant of the present invention or vinorelbine form solid dispersion.Generally speaking, the use at the field of pharmaceutical preparations solid dispersions technique is known.Thereby the first cause of exploitation solid dispersion is based on the probability that the dissolution of the active component of the not soluble in water and dosage forms for oral administration of raising improves bioavailability potentially.
The use of hydrophilic polymer such as Polyethylene Glycol, polyvinylpyrrolidone or cellulose derivative trends towards causing this water solubilization.In the context of the invention, using solid dispersion is not the dissolution rate that is intended to increase active component.The soluble derivative of vinca alkaloids, particularly vinorelbine salt, more two tartrate are very easily water-soluble, and their wettability feature does not cause any problem.
But, unexpectedly, more stable according to the galenic form of the soluble derivative of vinca alkaloids of the present invention, particularly vinorelbine salt.
Therefore, the two tartrates of vinorelbine must remain below-15 ℃ temperature, regardless of its form (amorphous or crystallization) and its separating degree (do not grind, grinding or micronization).
On the other hand, the solution of the two tartrates of vinorelbine can remain on+5 ℃ to ± 3 ℃ temperature.All like this for this soft capsule filling solution of forming for the injection of aqueous solution that is used for ejection preparation with by liquid macrogol, glycerol, second alcohol and water.Therefore, solubilising operation has seemingly caused better stability.
Surprisingly, in pharmaceutical composition according to the present invention, dissolved soft capsule is the same stable therein with them at least for the two tartrates of the soluble derivative of the vinca alkaloids of dispersed powders state, particularly vinorelbine, even more stable.
The soluble derivative of vinca alkaloids, particularly vinorelbine, more especially the preparation of the dispersion of the two tartrates of vinorelbine usually starts from the Polyethylene Glycol that mixes this active component and molten condition.For this reason, described Polyethylene Glycol will be heated to the temperature a little more than its fusion temperature in advance, make it become liquid condition, thereby can under agitation mix with the soluble derivative of vinca alkaloids.This method ends at the cooling down operation of described dispersion, makes it become solid state.If use the Polyethylene Glycol of high molecular weight, preferably it is heated in the presence of plasticizer, this will make described solid polyethylene glycol become liquid condition and be no more than 80 ℃ of other temperature of level.
The first step of preparation solid dispersion is following carrying out advantageously:
-discontinuous mode: in jar, prepare, for example then mixture is divided in the hard gelatin capsule, or utilize technology such as injection molding, perhaps
-continuation mode: use the hot extrusion technology.
These technology have two advantages:
The concentration of active component in final mixture can be up to 60%, and it for example allows big unit dose,
The time of staying (this during it be exposed to high temperature) of active component in extruder is shorter, thereby can use vinorelbine salt, although it is to thermo-responsive, and high molecular weight polyethylene glycol.
The dispersion that obtains can be discrete form, piller form for example, or be integral form, for example tablet form.In order to protect producers or patient to avoid to be exposed to the risk of cytotoxicity vinorelbine salt, final medicament forms will be sub-packed in the hard gelatin capsule or they will be made into coated tablet.
Mix and cooling after, Polyethylene Glycol and vinorelbine become the material that can handle by different way according to required particular form.It can directly be inclined to hard gelatin capsule, obtains integral form after described hard gelatin capsule cooling.
Conventional, hard gelatin capsule is made up of the outer bacterial polysaccharides of gelatin, hydroxypropyl emthylcellulose and born of the same parents, and the outer bacterial polysaccharides of described born of the same parents uses Aureobasidium pullulans (Aureobasidium pullulans) to obtain known Pullulan by name.
According to a kind of alternatives of the inventive method, dispersion is sub-packed in the hard gelatin capsule by pouring into operation.
According to a kind of alternatives of the inventive method, the solid dispersion extruding with stable obtains the piller for the preparation of hard gelatin capsule or tablet.Under latter instance, in the actual fabrication operating process, carry out coating, for example use coextrusion techniques, dispersion is coextrusion with natural or synthetic film forming polymer effectively, directly obtains film-coated tablet.
Mode as an alternative, such coating operation also can for example require the production stage of fluid bed or turbine packaging technique carrying out in the additional production step afterwards.
In two kinds of coating alternatives, coating all can advantageously use the film forming polymer in natural or synthetic source to obtain, particularly cellulose derivative such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose or acrylate or modified methyl acrylic copolymer or high molecular weight polyethylene glycol.
When described stable solid dispersion uses low-molecular-weight (800-2000) Polyethylene Glycol, can add the technology additive, as structural agent (structuring agents), particularly silicon dioxide, poly(ethylene oxide), microcrystalline Cellulose.The ratio of these additional structure agent can change between 0.05% to 10%, preferred 0.5% to 5%.
At last, should be noted that when using high molecular weight polyethylene glycol, can advantageously add plasticizer avoiding the excessive increase of fusion temperature, thus they with the first married operation condition of Herba Catharanthi Rosei derivant under can obtain with liquid condition.The example of plasticizer comprises citrate, glycerol triacetate etc.
Following examples have been described some possible preparation and preparation methoies:
Embodiment 1:
Use semi-solid Polyethylene Glycol to relate to and mix structural agent such as silicon dioxide, as described in following compositions:
Two tartrate (amorphous form) 55.40mg of vinorelbine
Be vinorelbine 40.00mg
Silicon dioxide 3.00mg
Cetomacrogol 1000 qsq 330.00mg
Be prepared in discontinuous mode, the preliminary hot mixt of preparation is sub-packed in the gelatine capsule then in jar.
Embodiment 2:
Use the high melting solid Polyethylene Glycol to require to use plasticizer and use the hot extrusion preparation method.
In twin screw co-extrusion press, prepare following hot mixt in a continuous manner:
Two tartrate (amorphous form) 55.40mg of vinorelbine
Be vinorelbine 40.00mg
Triethyl citrate 6.00mg
Polyethylene glycol 6000 qsq 150.00mg
Following examples 3 have provided full-time instruction of the present invention and have described preparation method.It relates to the gelatine capsule that contains the 40mg vinorelbine that is scattered in the polyethylene glycol 1500.
Embodiment 3:
Definitely consisting of of content:
Two tartrate (amorphous form) 55.40mg of vinorelbine
Be vinorelbine 40.00mg
Polyethylene glycol 1500 qsq 330.00mg
1 of No. 2 gelatine capsule
Preparation method may further comprise the steps:
-polyethylene glycol 1500 is heated to 55 ℃ to 60 ℃ temperature,
-two the tartrates of dispersion vinorelbine under mechanical agitation,
-being filled in No. 2 hard gelatin capsules, every hard gelatin capsule is filled the 330mg mixture,
-be cooled to ambient temperature.
The neccessary composition of gelatine capsule shell is hydrophilic polymer, and it can be gelatin or hydroxypropyl emthylcellulose (HPMC) or Pullulan as mentioned above.
Owing in storage process, do not leak, therefore need not to seal gelatine capsule.But in view of the cytotoxicity of vinorelbine, suggestion should seal for safety reasons.This sprays by stretch package (stretch wrapping) or by water-pure spray and carries out.
Said composition has excellent physical and chemical stability: be formulated in the degraded of vinorelbine after 25 ℃/60%RH (severe temperatures condition) stores 6 months of the dispersion in the hard gelatin capsule:
-be less than the viewed degraded of independent vinorelbine very significantly,
-be less than or equal viewed degraded in soft capsule.
The result is expressed as follows:
After under the 25 ℃/60%RH 6 months, compare the variation (relative %) of impurity content with t0
Other hydrophilic polymeies such as Polyethylene Glycol have been tested.Vinorelbine is significantly lower in the stability in the presence of these other polymer: under the 25 ℃/60%RH only after 1 month, the variation of comparing impurity content with t0 is respectively for polyvinylpyrrolidone and cellulose ether+and 7.63% and+29.08%.
In addition, beat allly be that the dissolution rate that is included in the two tartrates of vinorelbine of the dispersity in the hard gelatin capsule of above embodiment 3 is very similar to the stripping kinetics that is included in the two tartrates of vinorelbine in the soft capsule with dissolved state.Six duplicate samples that in appended Figure 1A and 1B, provided each galenic form batch in 900ml water in 37 ℃, the stripping curve of 50rpm.Method therefor is the swivel plate method that provides among the European Pharmacopoeia 2.9.3.The two tartrates of vinorelbine are 100% complete stripping in less than 30 minutes.
The unit dose of the hard gelatin capsule of representing with alkaline vinorelbine is 5 to 100mg, advantageously equals 20mg, 30mg, 40mg and 80mg.
But by injection molding, the present invention can be used in particular for obtaining to surpass the unit dose that 100mg reaches 300mg.
Claims (14)
1. the soluble derivative of vinca alkaloids is stable solid dispersion in 1000 to 6000 the Polyethylene Glycol at least a molecular weight, the soluble derivative of wherein said vinca alkaloids is the two tartrates of vinorelbine, the mass ratio of the two tartrates of vinorelbine and the Polyethylene Glycol of next is 1.5: 1 to 1: 10, and described dispersion prepares by following operation:
-Polyethylene Glycol is heated to temperature a little more than its fusion temperature, make it become liquid condition, thus can under agitation mix with the soluble derivative of vinca alkaloids and
-under agitation the soluble derivative with the vinca alkaloids of powder type mixes with the Polyethylene Glycol that the preceding step obtains, the formation dispersion and
-with described dispersion cooling, make it become solid state.
2. according to the stable solid dispersion of claim 1, it is characterized in that: described dispersion also contains plasticizer or is selected from the structural agent of silicon dioxide, poly(ethylene oxide), microcrystalline Cellulose.
3. according to the stable solid dispersion of claim 1 or 2, it is characterized in that: it is integral form.
4. according to the stable solid dispersion of claim 3, it is characterized in that: described solid dispersion is sub-packed in the hard gelatin capsule.
5. according to the stable solid dispersion of claim 4, it is characterized in that: described solid dispersion is united compressible excipients, is tablet form.
6. according to the stable solid dispersion of claim 1 or 2, it is characterized in that: it is discrete piller form.
7. according to the stable solid dispersion of claim 6, it is characterized in that: described solid dispersion is the discrete piller form that is sub-packed in the hard gelatin capsule.
8. according to the stable solid dispersion of claim 1, it is characterized in that: described mass ratio is 1: 3 and 1: 6.
9. according to the stable solid dispersion of claim 2, it is characterized in that: when using solid polyethylene glycol, Polyethylene Glycol is heated in the presence of plasticizer is no more than 80 ℃ of maximum temperatures.
10. according to the stable solid dispersion of claim 2, it is characterized in that: when using molecular weight as the Polyethylene Glycol of 1000-2000, add the structural agent that is selected from silicon dioxide, microcrystalline Cellulose or poly(ethylene oxide) to dispersion.
11. the stable solid dispersion according to claim 1 is characterized in that: it requires described dispersion is sub-packed in the hard gelatin capsule by pouring into operation.
12. the stable solid dispersion according to claim 1 is characterized in that: with the dispersion extruding, obtain piller, with preparation tablet or hard gelatin capsule.
13. the stable solid dispersion according to claim 1 is characterized in that: dispersion and natural or synthetic film forming polymer is coextrusion, obtain film-coated tablet.
14. the stable solid dispersion according to claim 13 is characterized in that: film coating tablet prepares in fluid bed or turbine.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0414069 | 2004-12-30 | ||
| US11/025348 | 2004-12-30 | ||
| FR0414069A FR2880274B1 (en) | 2004-12-30 | 2004-12-30 | STABLE SOLID DISPERSION OF VINCA ALKALOID DERIVATIVE AND PROCESS FOR PRODUCING THE SAME |
| US11/025,348 US20060147518A1 (en) | 2004-12-30 | 2004-12-30 | Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it |
| PCT/EP2005/056965 WO2006069938A1 (en) | 2004-12-30 | 2005-12-20 | Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101087591A CN101087591A (en) | 2007-12-12 |
| CN101087591B true CN101087591B (en) | 2013-07-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200580044730.0A Active CN101087591B (en) | 2004-12-30 | 2005-12-20 | Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN101087591B (en) |
| FR (1) | FR2880274B1 (en) |
| NO (1) | NO339809B1 (en) |
| ZA (1) | ZA200704669B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267179A (en) * | 2014-07-08 | 2016-01-27 | 东曜药业有限公司 | Stable solid pharmaceutical composition including water-soluble vinorelbine salt and preparation method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2918566B1 (en) | 2007-07-11 | 2009-10-09 | Pierre Fabre Medicament Sa | STABLE PHARMACEUTICAL COMPOSITION OF A WATER SOLUBLE SALT OF VINFLUNINE. |
| WO2009105937A1 (en) * | 2008-02-29 | 2009-09-03 | 江苏豪森药业股份有限公司 | A vinorelbine soft capsule and its preparation method and application. |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003101383A2 (en) * | 2002-05-31 | 2003-12-11 | R.P. Scherer Technologies, Inc. | Oral pharmaceutical composition for soft capsules containing vinorelbine and method of treatment |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HN1998000115A (en) * | 1997-08-21 | 1999-06-02 | Warner Lambert Co | SOLID PHARMACEUTICAL DOSAGE FORMS |
| DE10000792A1 (en) * | 2000-01-11 | 2001-07-19 | Bernhard C Lippold | Formulations of active substances in the form of a solid dispersion |
| AU2001268338A1 (en) * | 2000-06-12 | 2001-12-24 | Smith Kline Beecham Corporation | Novel solid dispersion compositions |
| US20030212102A1 (en) * | 2001-06-12 | 2003-11-13 | Koretke Todd W | Novel solid dispersion compositions |
-
2004
- 2004-12-30 FR FR0414069A patent/FR2880274B1/en active Active
-
2005
- 2005-12-20 CN CN200580044730.0A patent/CN101087591B/en active Active
-
2007
- 2007-06-26 ZA ZA200704669A patent/ZA200704669B/en unknown
- 2007-06-27 NO NO20073316A patent/NO339809B1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003101383A2 (en) * | 2002-05-31 | 2003-12-11 | R.P. Scherer Technologies, Inc. | Oral pharmaceutical composition for soft capsules containing vinorelbine and method of treatment |
Non-Patent Citations (2)
| Title |
|---|
| 陆彬.药物新剂型与新技术 1.人民卫生出版社,2002,3、11页. |
| 陆彬.药物新剂型与新技术 1.人民卫生出版社,2002,3、11页. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267179A (en) * | 2014-07-08 | 2016-01-27 | 东曜药业有限公司 | Stable solid pharmaceutical composition including water-soluble vinorelbine salt and preparation method thereof |
| CN105267179B (en) * | 2014-07-08 | 2020-04-03 | 东曜药业有限公司 | Stable solid pharmaceutical composition comprising a water-soluble vinorelbine salt and process for preparing same |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200704669B (en) | 2008-08-27 |
| FR2880274B1 (en) | 2007-04-13 |
| NO20073316L (en) | 2007-06-27 |
| FR2880274A1 (en) | 2006-07-07 |
| CN101087591A (en) | 2007-12-12 |
| NO339809B1 (en) | 2017-02-06 |
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