WO2006091180A2 - Fucoidan multiparticulate drug carrier systems - Google Patents
Fucoidan multiparticulate drug carrier systems Download PDFInfo
- Publication number
- WO2006091180A2 WO2006091180A2 PCT/TR2005/000015 TR2005000015W WO2006091180A2 WO 2006091180 A2 WO2006091180 A2 WO 2006091180A2 TR 2005000015 W TR2005000015 W TR 2005000015W WO 2006091180 A2 WO2006091180 A2 WO 2006091180A2
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- WIPO (PCT)
- Prior art keywords
- chitosan
- fucoidan
- solution
- drug carrier
- value
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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
- A61K9/14—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
-
- 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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
Definitions
- This invention is related with the preparation of multiparticulates: a drug carrier system to inject the drugs into human body.
- Multiparticulate systems are defined as spherules, which according to the preparation technique are drug encapsulated in polymer/s or dispensed in the polymer system and carried within the body and the sizes vary between nanometer to millimeter.
- polymers are used. Polymers, in its simplest definition, are a high amount of the same or various atoms with chemical bounds, bounded together more or less regularly to form a long chained and thus high molecular weight compounds. These structures are synthetic, semi-synthetic or natural and all are used for the preparation of multiparticulate systems.
- Multiparticulate systems are made of compounds embodying complexes formed by polymer/s and pharmaceutically active agents.
- Onto other polycationic polymers chitosan and its salt or a derivative, which mostly has a polysaccharide structure, is preferred as the polycationic polymers for use.
- a carrier preferably pharmaceutically acceptable within the current status of the technique; like oligonucleotide; a negative loaded pharmacologically effective agent and with a polycationic polymer, like chitosan or chitosan salt or a derivative
- the drug is encapsulated and injected into the body and controlled release is obtained and the agent is protected from exterior effects.
- a polycationic polymer like chitosan or chitosan salt or a derivative
- WO 03/030941 discloses the controlled release drug compounds, that includes polycationic polymers like chitosan and negative loaded pharmaceutically active substances.
- Chinese patent numbered 1293952 discloses the preparation of microparticulates by mixture of chitosan and fibroin and the use of this microparticulate in controlled release of drugs.
- the object of this invention is not only the preparation of fucoidan multiparticulate system without the need of organic solvent and excipients as catalysts, but also to accomplish that in a very short time and with a very simple preparation procedure.
- the fucoidan multiparticulate systems with its being used as a drug carrier system for the first time and without the need for organic solvents and any excipients as catalysts, and its very short and simple preparation period is an improvement regards to multiparticulate systems.
- Chitosan as a natural polymer which has a biological solubility, is very important as a cationic polymer that takes part in the structures of controlled release systems in the injection of high molecular weight substances such as protein-peptides to human body.
- the primary basis of this system is made up of fucoidan, a polysaccharide; which is obtained from algae and due to the sulfates in its structure shows an anionic character.
- Fucoidan multiparticulate systems are prepared via the combination of fucoidan, which shows a strong anionic character and chitosan another polysaccharide, which shows cationic character.
- chitosan which has a molecular weight between 10 to 1500 kD is solved in acid solvent and according to the size of the multiparticulates preferred to be obtained, mixed rather in a homogenizer or a low RPM stirrer.
- the fucoidan solution that is prepared with a suitable amount of bi-distilled or distilled water and has a pH value 5.0 to 7.0 is slowly added onto chitosan, which is being stirred and has a pH value 1.0 to 7.0.
- the mixture ratio of chitosan and fucoidan solutions is 0.1 : 5.0.
- the solution that includes 0.1% to 4.0% fucoidan and 0.1% to 5.0% chitosan is stirred in the homogenizer or the stirrer until the particles are formed. Then particles are centrifuged so that they are free of wastes, then washed and eliminated after they are lyophilized.
- BSA Bovine Serum Albumin
- chitosan that has a molecular weight between 100 to 1000 kD is solved in acid solution.
- the fucoidan solution that is prepared with bi-distilled or distilled water and has a pH value between 5.5 to 6.0 is added onto the chitosan solution that has turned into an acidic solution and stirred in a homogenizer or a low RPM stirrer and has a pH value between 2.0 to 5.0.
- the mixture ratio of chitosan and fucoidan solutions is 0.5: 2.0.
- the obtained solution has chitosan (0.25%, 0.50% and 0.75%), fucoidan (1.5%, 1.75% and 2.5%) and protein (0.25%, 0.50% and 0.75%) concentrations.
- Chitosan-fucoidan multiparticulates are prepared via the interaction of the oppositely loaded groups stirred in the homogenizer or stirrer. Then the morphological structure and particle sizes of the microparticulates that are centrifuged, washed and lyophilized are controlled.
- the BSA release of multiparticulates is realized at pH value 7.4, 37 ⁇ 0.1 °C in the PBS and the BSA content is established with spectrophotometric method, at 595 nm.
- the structural integrity of the BSA is checked by the SDS- PAGE.
- chitosan-fucoidan microparticulates which are BSA loaded and have particle sizes between 0.61-1.23 micrometers and have spherical structures.
- Figure 1 and Figure 2 show the Scanning Electron Microscopy (SEM) photographs of the chitosan-fucoidan microparticulates which are BSA loaded).
- SEM Scanning Electron Microscopy
- the encapsulation efficiency of the microparticulates varies between 51.8% and 89.5%. The highest efficiency of encapsulation is obtained from multiparticulates that include 2.5% of fucoidan.
- Chitosan, fucoidan and BSA concentrations affect the protein release from multiparticulates.
- the origin of chitosan is important in BSA release. When the chitosan concentration is increased a decreasing effect in the release is observed. When the protein quantity is decreased an increase in BSA release is observed.
- the specifications of the microparticulates could be modulated via the changes in the formula variables.
- the fucoidan multiparticulate which is a scope of invention in drug carrier systems increases the convenience in industry with its no need of organic solvents and excipients such as catalysts, its very short duration and simple preparation method and low cost.
- the release time was extended up to 6 days for fucoidan microspheres prepared at two different rpm rates, and while the effect of high amount drug release within the first hours called burst effect was decreased to 20%, this effect was decreased to 42% at most for the crosslinked chitosans, however it was seen that whole drug was released within the first 8 hours in the non-crosslinked chitosan formulations.
- drug release for fucoidan microspheres complied with the 0 degree kinetic after the first 8 hours, for chitosan micro particles, such a release kinetic was not seen, on the contrary, for the crosslinked chitosan microspheres, a triphasic release profile was seen.
Abstract
As a drug carrier system, the fucoidan multiparticulate systems are prepared with the interaction of fucoidan; a polysaccharide has an anionic character with chitosan also a polysaccharide and demonstrates cationic characteristics. In the preparation of these multiparticulate systems, neither organic solvents nor excipients are used as catalysts.
Description
DESCRIPTION
FUCOIDAN MULTIPARTICULATE DRUG CARRIER SYSTEMS
Technical Field
This invention is related with the preparation of multiparticulates: a drug carrier system to inject the drugs into human body.
Background Art It is very hard to effectively inject pharmaceutical complexes that include substances with high molecular weights, like proteins and peptides into the body. The reason is they cannot penetrate through the biological membrane and barriers effectively due to their high molecular weights. This well known issue of the technique is solved with multiparticulate systems.
Multiparticulate systems are defined as spherules, which according to the preparation technique are drug encapsulated in polymer/s or dispensed in the polymer system and carried within the body and the sizes vary between nanometer to millimeter. In the preparation of the multiparticulate systems, as mentioned above, polymers are used. Polymers, in its simplest definition, are a high amount of the same or various atoms with chemical bounds, bounded together more or less regularly to form a long chained and thus high molecular weight compounds. These structures are synthetic, semi-synthetic or natural and all are used for the preparation of multiparticulate systems.
Multiparticulate systems are made of compounds embodying complexes formed by polymer/s and pharmaceutically active agents. Onto other polycationic polymers, chitosan and its salt or a derivative, which mostly has a polysaccharide structure, is preferred as the polycationic polymers for use.
In a carrier, preferably pharmaceutically acceptable within the current status of the technique; like oligonucleotide; a negative loaded pharmacologically effective agent and with a polycationic polymer, like chitosan or chitosan salt or a derivative, the drug is encapsulated and injected into the body and controlled release is obtained and the agent is protected from exterior effects.
In the prior art, there are a few methods to prepare particulate systems. As an example, American Patent no: 4,946,870 defines a carrier system that includes pharmaceutical agents and chitosan or aminopolysaccharides like chitosan derivatives. International application numbered WO 03/030941 discloses the controlled release drug compounds, that includes polycationic polymers like chitosan and negative loaded pharmaceutically active substances. Chinese patent numbered 1293952, discloses the preparation of microparticulates by mixture of chitosan and fibroin and the use of this microparticulate in controlled release of drugs.
The multiparticulate system preparation methods mentioned within the current status of the technique, have rarely been applied in the industry due to the requirement of expensive technologies, lack of correction of the toxicity problems of the few and the requirement of complicated preparation methods for some other. For example; due to the complicated preparation methods of multiparticulate systems, encapsulation of substances like proteins/peptides, which have higher molecular weights, also bring problems; i.e.: structural or conformational changes. When the types of preparation methods of multiparticulate systems are reviewed, it is acknowledged that methods, such as pellet, nano/microparticulate, and microsponge are widely used in the industry. However, there are very few number of preparates in the market. The major reasons are; they are new systems, there are still unsolved issues, the preparation procedures are time taking and the cost is high.
As an example to the processes explained in the preparation of multiparticulate systems in the prior art; water dehydration for highly water soluble drugs (US 4,652,441), emulsion - solvent vaporization for drugs insoluble in water (US 4,389,330), for water soluble and insoluble drugs complex coaservation - phase separation (US 5,603,960), spray drying, (US 5,622,657), solvent extraction (US 4,389,330), micelle polymerization (US 5,705,197) and Wurster method could be given.
Very few of them are preferred in the industry, since in the preparation of the procedures organic solvents and excipients are used.
Object of the Invention
The object of this invention is not only the preparation of fucoidan multiparticulate system without the need of organic solvent and excipients as catalysts, but also to accomplish that in a very short time and with a very simple preparation procedure.
Description of the Invention
The fucoidan multiparticulate systems, with its being used as a drug carrier system for the first time and without the need for organic solvents and any excipients as catalysts, and its very short and simple preparation period is an improvement regards to multiparticulate systems.
Chitosan as a natural polymer, which has a biological solubility, is very important as a cationic polymer that takes part in the structures of controlled release systems in the injection of high molecular weight substances such as protein-peptides to human body. On the other hand, the primary basis of this system is made up of fucoidan, a polysaccharide; which is obtained from algae and due to the sulfates in its structure shows an anionic character. Fucoidan multiparticulate systems are prepared via the combination of fucoidan, which shows a strong anionic character and chitosan another polysaccharide, which shows cationic character.
According to procedure that is the scope of the invention; chitosan which has a molecular weight between 10 to 1500 kD is solved in acid solvent and according to the size of the multiparticulates preferred to be obtained, mixed rather in a homogenizer or a low RPM stirrer. The fucoidan solution that is prepared with a suitable amount of bi-distilled or distilled water and has a pH value 5.0 to 7.0 is slowly added onto chitosan, which is being stirred and has a pH value 1.0 to 7.0. The mixture ratio of chitosan and fucoidan solutions is 0.1 : 5.0. The solution that includes 0.1% to 4.0% fucoidan and 0.1% to 5.0% chitosan is stirred in the homogenizer or the stirrer until the particles are formed. Then particles are centrifuged so that they are free of wastes, then washed and eliminated after they are lyophilized.
Examplei
In this example BSA (Bovine Serum Albumin) is used as the model protein to examine the in vitro characteristics of the chitosan-fucoidan multiparticulate systems. First, chitosan
that has a molecular weight between 100 to 1000 kD is solved in acid solution. The fucoidan solution that is prepared with bi-distilled or distilled water and has a pH value between 5.5 to 6.0 is added onto the chitosan solution that has turned into an acidic solution and stirred in a homogenizer or a low RPM stirrer and has a pH value between 2.0 to 5.0. The mixture ratio of chitosan and fucoidan solutions is 0.5: 2.0. The obtained solution has chitosan (0.25%, 0.50% and 0.75%), fucoidan (1.5%, 1.75% and 2.5%) and protein (0.25%, 0.50% and 0.75%) concentrations.
Chitosan-fucoidan multiparticulates are prepared via the interaction of the oppositely loaded groups stirred in the homogenizer or stirrer. Then the morphological structure and particle sizes of the microparticulates that are centrifuged, washed and lyophilized are controlled. The BSA release of multiparticulates is realized at pH value 7.4, 37±0.1 °C in the PBS and the BSA content is established with spectrophotometric method, at 595 nm.
After the preparation process, the structural integrity of the BSA is checked by the SDS- PAGE.
With the process explained in this sample, chitosan-fucoidan microparticulates, which are BSA loaded and have particle sizes between 0.61-1.23 micrometers and have spherical structures, are obtained. (Figure 1 and Figure 2 show the Scanning Electron Microscopy (SEM) photographs of the chitosan-fucoidan microparticulates which are BSA loaded). The encapsulation efficiency of the microparticulates varies between 51.8% and 89.5%. The highest efficiency of encapsulation is obtained from multiparticulates that include 2.5% of fucoidan. Chitosan, fucoidan and BSA concentrations affect the protein release from multiparticulates. The origin of chitosan is important in BSA release. When the chitosan concentration is increased a decreasing effect in the release is observed. When the protein quantity is decreased an increase in BSA release is observed. The specifications of the microparticulates could be modulated via the changes in the formula variables.
The fucoidan multiparticulate which is a scope of invention in drug carrier systems increases the convenience in industry with its no need of organic solvents and excipients such as catalysts, its very short duration and simple preparation method and low cost.
Above preferred drug carrier system is not considered as limiting the protection scope of the invention. In the view of the information disclosed with the invention, any changes to
take part on this preferred drug carrier system, should be evaluated in the protection scope of the invention. Example 2
In other study, ofloxacin, a flouroquinolone group antibiotic, was encapsulated by fucoidan microspheres and in vitro drug retention and release capacity of microparticular system was investigated in comparison to chitosan microspheres. Fucoidan microspheres, which were used at a rate of 1.0% (w/v) in the performed study, were prepared at two different rotation speeds, 400 and 23.000 rpm, by mixing with chitosan solution. On the other hand, chitosan microspheres were prepared with the addition of external phase containing sodium sulphate and ofloxacin to internal phase at the same rpm in both crosslinked and non-crosslinked manner. As a result, it has been determined that drug retention for fucoidan-based microspheres was found to be 94.3% but for chitosan microspheres prepared without cross linkage, this value increased up to 75.8% at most when 1.0% chitosan solution was used whereas this value declined too much (70.2 to 48.8%) when chitosan solutions with lower concentrations were used, and for crosslinked chitosan microspheres, this value could rose up to 81.2% at most. The results with which the actual difference was seen have been related with the controlled release of ofloxacin from the system. The release time was extended up to 6 days for fucoidan microspheres prepared at two different rpm rates, and while the effect of high amount drug release within the first hours called burst effect was decreased to 20%, this effect was decreased to 42% at most for the crosslinked chitosans, however it was seen that whole drug was released within the first 8 hours in the non-crosslinked chitosan formulations. In addition, while it was seen that drug release for fucoidan microspheres complied with the 0 degree kinetic after the first 8 hours, for chitosan micro particles, such a release kinetic was not seen, on the contrary, for the crosslinked chitosan microspheres, a triphasic release profile was seen. In the size analysis of microspheres, it was detected that the smallest fucoidan particles prepared at 400 rpm were ~ 1.0μ, crosslinked chitosan microspheres were ~ 2.5μ, and non-crosslinked chitosan microspheres were ~ 2.8μ. Differently, for fucoidan microspheres prepared at 23.000 rpm, nano level was reached and it was detected that the size was about 300 - 500 nm.
Again, encapsulation study with the same antibiotic was performed with lactic and glycolic acid, and copolymers in many times but the burst effect problem of the system arising also from the properties of polymers could not be solved and the values increased up to
Claims
1. Nano/microparticulate, pellet, bead, microsponge preparation methods for multiparticulate drug carrier system, characterized by containing two polymers of which one is anionic and the other is cationic.
2. A method according to claim 1 , characterized by being used in the transmission of high molecular weight substances.
3. A method according to claim 1 , wherein the polymer with anionic character is fucoidan.
4. A method according to claim 1 , wherein the polymer with cationic character is chitosan.
5. A method according to claim 3, wherein the fucoidan is fucoidan solution.
6. A method according to claim 4, wherein the chitosan is an acidic chitosan solution.
7. A method according to claim 1 , wherein the fucoidan solution and chitosan solution are mixed.
8. A method according to claim 7, wherein the pH value of the fucoidan solution is between 5-7.
9. A method according to claim 8, wherein the pH value of the fucoidan solution is between 5.5-6.
10. A method according to claim 7, wherein the pH value of the chitosan solution is between 1.0-7.0.
1 1. A method according to claim 10, wherein the pH value of the chitosan solution is between 2.0-5.0.
12. A method according to claim 4, wherein the molecular weight of chitosan is between 10-150O kD.
13. A method according to claim 12, wherein the molecular weight of chitosan is between 100-100O kD.
14. A method according to claim 7, wherein wherein the solution includes fucoidan between 0.1% and 4.0%.
15. A method according to claim 14, wherein wherein the solution includes fucoidan between 0.2% and 3.0%.
16. A method according to claim 7, wherein the acidic solution includes chitosan between 0.1% and 5.0%.
17. A method according to claim 16, wherein the acidic solution includes chitosan between 0.15% and 3.0%.
18. A method according to claim 7, wherein the mixture ratio of Chitosan solution and fucoidan solution is 0.1 :5.0
19. A method according to claim 18, wherein the mixture ratio of Chitosan solution and fucoidan solution is 0.5:2.0
20. A method according to claim 1 , characterized by being used in pharmaceuticals, cosmetics and nutrition.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015161192A1 (en) * | 2014-04-17 | 2015-10-22 | Memorial Sloan Kettering Cancer Center | Fucoidan nanogels and methods of their use and manufacture |
CN106176666A (en) * | 2016-07-14 | 2016-12-07 | 青岛吉海营养科技有限公司 | A kind of anti-moisture absorption fucoidin product and preparation method thereof |
WO2018201981A1 (en) * | 2017-05-01 | 2018-11-08 | 中国医药大学 | Immunomagnetic composition, preparation method and use thereof, and kit for treating cancer |
US10383891B2 (en) * | 2014-10-06 | 2019-08-20 | Algamed Therapeutics (A.M.T) Ltd. | Compositions comprising sulfated polysaccharides and uses thereof |
CN110269842A (en) * | 2019-07-03 | 2019-09-24 | 中国人民解放军陆军军医大学第二附属医院 | A kind of natural nano grain preparation of anti-oxidation stress and preparation method thereof |
US10736964B2 (en) | 2017-05-01 | 2020-08-11 | China Medical University | Immunomagnetic nanocapsule and kit for treating cancer |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2015161192A1 (en) * | 2014-04-17 | 2015-10-22 | Memorial Sloan Kettering Cancer Center | Fucoidan nanogels and methods of their use and manufacture |
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WO2018201981A1 (en) * | 2017-05-01 | 2018-11-08 | 中国医药大学 | Immunomagnetic composition, preparation method and use thereof, and kit for treating cancer |
US10736964B2 (en) | 2017-05-01 | 2020-08-11 | China Medical University | Immunomagnetic nanocapsule and kit for treating cancer |
CN110269842A (en) * | 2019-07-03 | 2019-09-24 | 中国人民解放军陆军军医大学第二附属医院 | A kind of natural nano grain preparation of anti-oxidation stress and preparation method thereof |
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