US20080214497A1 - Water dispersible policosanol cyclodextrin complex and method of its production - Google Patents
Water dispersible policosanol cyclodextrin complex and method of its production Download PDFInfo
- Publication number
- US20080214497A1 US20080214497A1 US12/070,195 US7019508A US2008214497A1 US 20080214497 A1 US20080214497 A1 US 20080214497A1 US 7019508 A US7019508 A US 7019508A US 2008214497 A1 US2008214497 A1 US 2008214497A1
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- United States
- Prior art keywords
- policosanol
- complex
- cyclodextrin
- water dispersible
- surfactant
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
Disclosed is a formulation of policosanol with natural cyclodextrins resulting in a water dispersible form of policosanol. The disclosed process provides an economical commercial method for making the policosanol complex. The complex is suitable for incorporation into oral dosage forms and also in functional foods. One aspect of the present disclosure is a process for making a water dispersible policosanol cyclodextrin complex for animal ingestion. This method includes preparing a policosanol cyclodextrin complex and administering said complex to an animal. The preferred animal is a human with the route of administration being oral ingestion. The form of the complex for ingestion can be a hard gelatin capsule, tablet or wafers, which may contain other ingredients, both active and inactive. The complex also can be further formulated with excipients suitable for soft gelatin capsules, such as, for example, vegetable oils, waxes, lecithin, and surfactants such as Tween-80.
Description
- This application claims benefit of provisional application Ser. No. 60/901,533 filed on Feb. 15, 2007, the disclosure of which is expressly incorporated herein by reference.
- Not applicable.
- The present disclosure generally relates to development of water dispersible policosanol-cyclodextrin complexes for use in nutritional supplements and functional foods.
- Cyclodextrins (sometimes abbreviated herein as “CD” or “CD's”) are cyclic oligosaccharides composed of 6, 7, or 8 α-(1-4)-linked anhydroglucose units. The α-, β-, and γ-cyclodextrins prepared from starch are considered natural and are GRAS according to the USFDA. The cyclodextrins are widely used in the pharmaceutical industry to improve dissolution, stability and uptake of lipophilic molecules.
- Policosanol is a complex mixture of lipophilic very long-chain alcohols (C24-C34) isolated from waxes, such as, for example, sugarcane wax, rice bran wax, or beeswax. Typical commercially available policosanol contains 90% minimum fatty alcohols. The content of individual alcohols vary based on the source of wax and the process of isolation. The fatty alcohols in policosanol are primarily tetracosanol (0.5%-10%), hexacosanol (2%-15%), octacosanol (20%-70%), and triacontanol (5%-20%), while eicosanol, docosanol, heptacosanol, nonacosanol, dotriacontanol, tetratriacontanol, and hexatriacontanol make up the remaining minor constituents.
- Policosanol is used as a natural supplement to lower total cholesterol and low-density lipoproteins and raise high-density lipoproteins. Policosanol is a highly lipophilic material, insoluble in water and has poor bioavailability in humans. Policosanol has been reported to reduce cholesterol synthesis in vitro in cell cultures (Singh, DK, Li, L, and Porter, TD, Policosanol inhibits cholesterol synthesis in hepatoma cells by activation of AMP-kinase, J Pharmacol Exp Ther. 2006, 318:1020-6; Menendez R, Amor A M, Rodeiro I, Gonzalez R M, Gonzalez P C, Alfonso J L, Mas R, Policosanol modulates HMG-CoA reductase activity in cultured fibroblasts, Arch Med Res. 2001, 32:8-12). However, in human studies the results have been variable with minimal uptake of policosanol. It has been suggested that the lower and variable efficacy of poilcosanols in human studies can be due to their poor absorption from conventional delivery systems used in the industry. Hence it is desirable to develop an effective delivery system, which is commercially feasible in a cost sensitive supplement industry.
- The present disclosure is a formulation of policosanol with natural cyclodextrins resulting in a water dispersible form of policosanol, thereby improving bioavailability. The disclosed process provides an economical commercial method for making the policosanol complex. The complex is suitable for incorporation into oral dosage forms and also in functional foods.
- One aspect of the present disclosure is a process for making a water dispersible policosanol cyclodextrin complex for animal ingestion. This method includes preparing a policosanol cyclodextrin complex and administering said complex to an animal. The preferred animal is a human with the route of administration being oral ingestion. The form of the complex for ingestion can be a hard gelatin capsule, tablet or wafers, which may contain other ingredients, both active and inactive. The complex also can be further formulated with excipients suitable for soft gelatin capsules, such as, for example, vegetable oils, waxes, lecithin, and surfactants such as, for example, Tween-80.
- For a fuller understanding of the nature and advantages of the present invention, reference should be had to the following detailed description taken in connection with the accompanying drawings, in which:
-
FIG. 1 represents the DSC profile of free Policosanol; -
FIG. 2 represents the DSC profile of alpha-CD; -
FIG. 3 represents the DSC profile of physical mixture of alpha-CD +Policosanol; -
FIG. 4 represents the DSC profile of alpha-CD Policosanol complex; and -
FIG. 5 represents the TGA overlay of Policosanol, alpha-CD, Physical mixture and the complex. - The drawings will be described in further detail in the examples below.
- The present disclosure describes a method for making a water dispersible form of policosanol complexed with α-, β- or γ-cyclodextrin for use in the nutritional supplement, food, and pharmaceutical industry. Commercially available policosanol from sugarcane, rice bran, and beeswax containing 20%-70% Octacosanol was used for complexation. The molecular weight of Octacosanol was used to calculate the molar ratio. The molar ratio of cyclodextrin to policosanol can range, for example, from about 0.5:1 to about 10:1, and preferably from about 1:1 to about 2:1 for commercial production. The policosanol concentration in the complex can range, for example, from about 3% to about 40% (w/w). The policosanol/cyclodextrin complex (1:2 molar) was prepared using an aqueous slurry method. Policosanol was mixed with a non-ionic surfactant, such as, for example, Tween-80. The amount of surfactant can range between about 0.1% to about 15% by weight of policosanol, preferably between about 10% and about 15%. Heating to 70° C. melted the mixture. The cyclodextrin was dissolved in water (1:6 w/v) by heating to 70° C. The policosanol surfactant mixture was added to the cyclodextrin solution under high-speed homogenization using a Silverson high shear mixer. The complex started to precipitate out of solution after about 20 to about 30 minutes. The solution was allowed to come to room temperature and stirred overnight using an overhead stirrer. The properties of the complex can be further improved by the addition of, for example, bioadhesive polymers to the slurry before drying. The slurry can be dried by any commercial drying methods such as, for example, freeze-drying, spray-drying, or vacuum-drying.
- The aqueous slurry was dried by freeze-drying using a semi-commercial tray freeze dryer (Virtis). The product obtained was a white free flowing powder suitable for capsules, tablets, and/or further formulation compounding. The dried product can be micronized or ground and/or sieved to form a uniform powder suitable for further applications or formulations.
- The interaction of cyclodextrins with policosanol and the quantification of amount of policosanol complexed were determined by Differential Scanning Calorimetry (DSC) and Thermo Gravimetric Analysis (TGA). The DSC is based on the disappearance of the melting peak or a reduction in the melting peak area of the guest molecule. The amount of complexation can be calculated based on the melting peak area of the guest molecule before and after complexation. The TGA gives an indication of the interaction between the guest and cyclodextrins. The complex may be more thermo stable as compared to the free guest molecule or a physical mixture of the guest and cyclodextrin. The techniques have been widely used to study the complexation of cyclodexrins with various guest molecules (Rossel, C. P., Carreno, J. S., Rodriguez-Baeza, M., and Alderete, J. B., Inclusion complex of the antiviral drug acyclovir with cyclodextrin in aqueous solution and in solid phase, Quimica Nova, 23(6): 749-752, 2000; Zuo, Z., Kwon, G., Stevenson, B., Diakur, J., and Wiebe, L. I., J. Pharm. Pharmceut Sci., Flutamide-hydroxypropyl-beta-cyclodextrin complex: Formulation, physical characterization and absorption studies using the Caco-2 in vitro model, 3(2): 220-227, 2000).
- While the water dispersible policosanol cyclodextrin complex has been described with reference to various embodiments, those skilled in the art will understand that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope and essence of the disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from the essential scope thereof. Therefore, it is intended that the water dispersible policosanol cyclodextrin complex not be limited to the particular embodiments disclosed, but that the water dispersible policosanol cyclodextrin complex will include all embodiments falling within the scope of the appended claims. In this application all units are in the metric system and all amounts and percentages are by weight, unless otherwise expressly indicated. Also, all citations referred herein are expressly incorporated herein by reference.
- 51 g alpha-CD was dissolved in 300 ml of water by heating to 70° C. 10 g of sugarcane Policosanol was mixed with 1.5 g of Tween-80 (also known as
Polysorbate 80, is a mixture oleate esters of sorbitan polyethoxylates) and melted by heating to 70° C. The oily mixture was added to the CD solution under homogenization. After 30 min of homogenization, the complex started to precipitate out of solution. The mixture was cooled to room temperature and stirred overnight using an overhead stirrer. The slurry was freeze-dried to obtain a white water dispersible powder containing 16% policosanol. - The DSC analysis was conducted using TA Instruments 2920 in an inert atmosphere.
FIGS. 1-4 present the DSC profiles of Policosanol, alpha-CD, policosanol+alpha-CD physical mixture and the complex respectively. Policosanol showed a major melting endotherm at 81.9° C. The area of the endotherm, which is proportional to the free Policosanol, makes it possible to quantify the complexing. Policosanol delta-H=156.4 j/g; uncomplexed Policosanol in complex delta-H=15.70 j/g. Uncomplexed Policosanol, 10%.FIG. 5 presents the TGA overlay of Policosanol, alpha-CD, policosanol+alpha-CD physical mixture and the complex. The complex showed more thermal stability than the free Policosanol and the physical mixture. - 62 g beta-CD was dissolved in 300 ml of water by heating to 70° C. 10 g of sugarcane Policosanol was mixed with 1.5 g of Tween-80 and melted by heating to 70° C. The oily mixture was added to the CD solution under homogenization. After 30 min of homogenization, the complex started to precipitate out of solution. The mixture was cooled to room temperature and stirred overnight using an overhead stirrer. The slurry was freeze-dried to obtain a white water dispersible powder containing 14% policosanol. The DSC analysis indicated the uncomplexed Policosanol as 9%.
- 69.5 g gamma-CD was dissolved in 300 ml of water by heating to 70° C. 10 g of sugarcane Policosanol was mixed with 1.5 g of Tween-80 and melted by heating to 70° C. The oily mixture was added to the CD solution under homogenization. After 30 min of homogenization, the complex started to precipitate out of solution. The mixture was cooled to room temperature and stirred overnight using a overhead stirrer. The slurry was freeze-dried to obtain a white water dispersible powder containing 12.5% policosanol. The DSC analysis indicated the uncomplexed Policosanol as 11%.
Claims (20)
1. A water dispersible complex, which comprises:
water dispersible policosanol cyclodextrin complex in a molar ratio of cyclodextrin to policosanol ranging from about 0.5:1 to about 10:1.
2. The water dispersible complex of claim 1 , wherein said cyclodextrin is one or more of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.
3. The water dispersible complex of claim 1 , wherein policosanol is an isolate from one or more of sugarcane was, rice bran wax, or beeswax.
4. The water dispersible complex of claim 1 , wherein said molar ratio of cyclodextrin to policosanol ranges from between about 1:1 and about 2:1.
5. The water dispersible complex of claim 1 , which additionally comprises between about 0.1 wt-% and about 15 wt-% of a surfactant.
6. The water dispersible complex of claim 5 , which additionally comprises between about 10 wt-% and about 15 wt-% of said surfactant.
7. The water dispersible complex of claim 5 , wherein said surfactant comprises a non-ionic surfactant.
8. The water dispersible complex of claim 7 , wherein said surfactant is Tween-80.
9. The water dispersible complex of claim 1 , which has been dried to recover said complex as a powder.
10. The water dispersible complex of claim 9 , which has been dried by one or more of freeze-drying, spray-drying, or vacuum-drying.
11. A method for making a water dispersible complex, which comprises the steps of:
(a) forming a heated oily solution of policosanol and a surfactant;
(b) forming a heated aqueous solution of a cyclodextrin;
(c) mixing said oily solution under agitation to aqueous cyclodextrin solution to form a mixture; and
(d) cooling said mixture to form a complex precipitate.
12. The method of claim 11 , wherein said cooled mixture is dried to recover a complex precipitate powder.
13. The method of claim 11 , wherein the molar ratio of cyclodextrin to policosanol ranges from about 0.5:1 to about 10:1.
14. The method of claim 11 , wherein said cyclodextrin is one or more of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.
15. The method of claim 11 , wherein policosanol is an isolate from one or more of sugarcane was, rice bran wax, or beeswax.
16. The method of claim 11 , wherein said surfactant in step (a) ranges from between about 0.1 wt-% and about 15 wt-%.
17. The method of claim 16 , wherein said surfactant comprises a non-ionic surfactant.
18. The method of claim 17 , wherein said surfactant is Tween-80.
19. The method of claim 11 , wherein said complex precipitate is recovered as a powder by drying.
20. The method of claim 19 , wherein said drying comprises one or more of freeze-drying, spray-drying, or vacuum-drying.
Priority Applications (2)
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US12/070,195 US20080214497A1 (en) | 2007-02-15 | 2008-02-15 | Water dispersible policosanol cyclodextrin complex and method of its production |
US12/957,525 US8435967B2 (en) | 2007-02-15 | 2010-12-01 | Water dispersible policosanol cyclodextrin complex and method of its production |
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US90153307P | 2007-02-15 | 2007-02-15 | |
US12/070,195 US20080214497A1 (en) | 2007-02-15 | 2008-02-15 | Water dispersible policosanol cyclodextrin complex and method of its production |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103409247A (en) * | 2013-08-23 | 2013-11-27 | 吴江市利达上光制品有限公司 | Mosquito-expelling washing powder |
CN111000811A (en) * | 2019-12-31 | 2020-04-14 | 济南大学 | Orally rapidly disintegrating tablet containing policosanol |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109588497B (en) * | 2018-12-26 | 2020-08-21 | 淮阴工学院 | Antioxidant edible oleogel and preparation method thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5555555A (en) * | 1993-01-19 | 1996-09-10 | Aisin Seiki Kabushiki Kaisha | Apparatus which detects lines approximating an image by repeatedly narrowing an area of the image to be analyzed and increasing the resolution in the analyzed area |
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AU2003241477A1 (en) * | 2002-06-10 | 2003-12-22 | Elan Pharma International, Ltd. | Nanoparticulate polycosanol formulations and novel polycosanol combinations |
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2008
- 2008-02-15 US US12/070,195 patent/US20080214497A1/en not_active Abandoned
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Patent Citations (1)
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US5555555A (en) * | 1993-01-19 | 1996-09-10 | Aisin Seiki Kabushiki Kaisha | Apparatus which detects lines approximating an image by repeatedly narrowing an area of the image to be analyzed and increasing the resolution in the analyzed area |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103409247A (en) * | 2013-08-23 | 2013-11-27 | 吴江市利达上光制品有限公司 | Mosquito-expelling washing powder |
CN111000811A (en) * | 2019-12-31 | 2020-04-14 | 济南大学 | Orally rapidly disintegrating tablet containing policosanol |
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US20110071110A1 (en) | 2011-03-24 |
US8435967B2 (en) | 2013-05-07 |
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Owner name: BIO-ACTIVES, LLC, MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MADHAVI, DODDABELE L.;KAGAN, DANIEL I.;REEL/FRAME:020824/0597;SIGNING DATES FROM 20080417 TO 20080418 Owner name: BIO-ACTIVES, LLC, MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MADHAVI, DODDABELE L.;KAGAN, DANIEL I.;SIGNING DATES FROM 20080417 TO 20080418;REEL/FRAME:020824/0597 |
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