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Alginates: The right chemistry for pharmaceutical applications
Rina Chokshi. Ph.D. Americas, Application Manager Ewing, NJ
Overview • Alginate biosynthesis and chemistry • Potential Critical Material Attributes − Mannuronic/Guluronic acid ratio & Blockiness • Gelation mechanisms • Applications − Anti reflux − Satiety and weight contro − Controlled Release − Nano-suspension and Solid dispersion − Enteric coating − Macroencapsulation (enteric soft gel). − Biomedical 2
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FMC -Long history of seaweed harvesting
Seaweeds have been used in Norway for centuries for soil improvement, fuel, nutrition and livestock feed. FMC Health and Nutrition has been harvesting brown seaweeds for extraction of alginate since 1943. Transition from manual cutting to mechanical harvesting started early 1960s
Brown seaweeds contain a range of ingredients that can potentially be utilized for the benefit of animal and human health. Alginate is used as a thickener and gel forming agent in food, pharmaceuticals and industrial applications. It is used as an active pharmaceutical ingredient (API). 3
FMC’s brown seaweed resources
Laminaria hyperborea
Laminaria japonica
Lessonia trabeculata Laminaria hyperborea Laminaria japonica Lessonia trabeculata Lessonia nigrescens Durvillaea antarctica
Lessonia nigrescens
Durvillaea antarctica 4
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Sustainability in harvesting
There is approx. 30-50 million MT of Laminaria hyperborea along the coast
Storms wash away approx. 6 million MT L.h. every year
FMC harvests approx. 150160.000 MT L.h./year
Laminaria hyperborea is a renewable resource, and is harvested in a sustainable way
No harvesting when sea-birds have eggs/chickens in their nests
Other countries are looking to Norway to copy sustainable resource management
Laminaria hyperborea at the Norwegian Coast Harvesting Storms 0,3 % 12 %
Total resources 50 mill MT
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Chemical composition
Alginate is a structural building unit in brown seaweeds Functionality is determined by chemical composition Alginate is a natural polysaccharide; biocompatible, biodegradable, and safe for consumption (GRAS, E400-405) 6
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Chemical composition of alginate: 2 Monomers Na+ -OOC
OH O
O HO
O (M monomer)
(1,4) ß-D-mannuronate O OH
Na+ -OOC
O OH (1, 4) -L-guluronate
O
(G monomer)
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Chemical composition of alginate: 3 Block types COOO
COO-
OH O
OH O O
OH O
OH O
OH
OH O
O OH
OH
-O O C
COO-
C O O --
G
G
G OH
O
HO
OOC
M
OH
O
O
O
OH
O
-O O C O
O
O O
O
HO O
HO
M
OH
HO
G M
M-Block
M
M
HO
O
HO
OH
-O O C
G -O O C
O
HO
G-Block
O
O
Alternating or mixed block
COO-
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The range of seaweed raw materials allows FMC to manufacture alginates with a broad range of functionality Raw material
FG
FM
Laminaria hyperborea (stem)
0.70
0.30
Lessonia trabeculata
0.67
0.33
Laminaria hyperborea (whole plant)
0.64
0.36
Laminaria hyperborea (leaf)
0.55
0.45
Laminaria digitata
0.41
0.59
Lessonia nigrescens
0.40
0.60
Macrocystis pyrifeira
0.39
0.61
Ascophyllum nodosum
0.36
0.64
Laminaria japonica
0.34
0.66
Durvillea potatorum
0.31
0.69
Durvillea antarctica
0.31
0.69
-O
O
OC
HO O
HO
O
(1 4 ) -D -m a n n u ro n a te
O OH -O
OC
O
O
OH
( 1 4 ) - L - g u lu r o n a t e
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Manufacturing process and salt incorporation SEAWEED RAW MATERIAL WASHING/GRINDING
Incorporation/neutralization is one key step in manufacturing process determining properties of final product; Alginic acid
Protacid
EXTRACTION
SCREENING/FILTERING
Na2CO3
Na-alginate*
K2CO3
K-alginate*
NH4CO3
NH4 –alginate*
MgCO3
Mg-alginate*
CaCO3
Ca-alginate
Propylene oxide
Propylene glycol alginate*
Other salts
Alginates with special functional properties
PRECIPITATION ALGINIC ACID INCORPORATION
DRYING/MILLING
BLENDING
FILLING/PACKING
QUALITY CONTROL
SHIPPING
*) Water soluble salts 10
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Various alginate grades available for applications Products
G /M ratio
Viscosity at 1% solution cps
Particle size
Salt
PROTANAL LFR5/60
65-75 / 25-35
3.5 -7
60 (250 micron)
Na-alg
PROTACID F120NM
65-75 / 25-35
Insoluble
120 (125 micron)
Alg acid
PROTANAL CR 8133
30-40 / 60-70
15-45
150 (106 micron)
Na-alg
MANUCOL LKX
30-40 / 60-70
60-170
240 (63 micron)
Na-alg
PROTANAL CR 8223
30-40 / 60-70
200-450
150 (106 micron)
Na-alg
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Alginate provides two basic functionalities Thickening i.e., viscosity, stabilization
…and Gelling
This gel contains less than 1% alginate and almost 99% water
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Alginates: Critical material attributes Alginate compositi on G:M ratio
Particle size
Viscosity Material Attribute
Concentr ation
Molecular weight 13
Viscosity of alginates at different concentrations
Viscosity (mPa.s)
30000 25000
Typical viscosity grades
20000
High Medium Low
15000 10000 5000 0 0.0
1.0
2.0
3.0
4.0
Concentration (%) Rule of thumb: * Double alginate concentration increases viscosity 8-10 times * Double viscosity by increasing concentration 20% 14
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Viscosity (mPa.s)
Viscosity of alginates at different temperatures 900 800 700 600 500 400 300 200 100 0
Typical viscosity grades High Medium Low
0
10
20
30
40
Temperature (oC)
50
60
Viscosities of 1.0% concentration at different temperatures
General point: Prepare concentrated solutions with warm or hot water to reduce viscosity for ease of handling 15
Alginate forms gel by crosslinkage of alginate chains with calcium – ”Egg-box” model, calcium/alginate interaction:
Mørch, Y.A., Novel alginate microcapsules for cell therapy: a study of the structure‐function relationships in native and structurally engineered alginates. 2008, Norwegian University of Science and Technology, Faculty of Natural Sciences and Technology, Department of Biotechnology: Trondheim.
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Controlled gel formation
Stage 1: Disperse and hydrate alginate
High shear mixing
Alginate powder
Ca2+
Sequestrant
Hydrated alginate Sodium alginate solution
Rule of thumb: * Assist dispersion by dry-blending with other powders or slurrying in oil * Sequestrant necessary unless calcium low or temperature above 70C 17
Controlled gel formation
Stage 2: Control calcium release for gelation
Ca2+
More Ca2+
Hydrated alginate
Alginate gel
Sodium alginate solution
Calcium alginate gel
Calcium salt Ca2+ Sequestrant
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Alginate applications Technical/Industrial
Pharmaceuticals • • • •
Anti-reflux Sustained drug release Dental Wound care
Food
• Stabilization − Juice, dressings, ice cream, spreads, …. • Gelling − Pimiento, onion rings, flans, bakery creams, caviar ... • Film formation − Meat and fish coatings, confectionary, …
• • • • • • • • • •
Textile printing Welding rods Paper coating Low ignition cigarette paper Water treatment Petfood Animal feed Encapsulation Can sealing Ceramics
Personal Care
• Face masks • Spa treatments • Castings
Biomedical (NovaMatrix) 19
Alginates in pharmaceutical applications - a few examples of brands and manufacturers: Application
Some Brands and Manufacturers
Anti-reflux
API in Gaviscon range (Reckitt Benckiser); Raftforming component in Acidex (Pinewood) TUMS (GSK), Maalox (Sanofi Aventis), Algicon and Algicote (Aventis) ,
Sustained Release
Isoptin/Biaxin/Dilacoron (Verapamil HCl, Abbott/Knoll), Nicorette Commit (GSK), Klacid/Klaricid (Clarithromycin, Abbott)
Dental Impression materials
Jeltrate (Dentsply), Cavex (Cavex), Algitray and OrthoPrint(Zhermack)
Wound care
Kaltostat (Convatec), ReliaMed (AMS), Coalgan (Brothier), NuDerm (J&J), AlgiSite (S+N), Tegagen (3M),
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Alginates in pharmaceutical applications Active ingredient Anti reflux Biomedical application
Targeted drug delivery
Satiety application
Alginates applications
Controlled release
Nanosuspension and Solid dispersion
In-situ gel formation Enteric coating
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Alginates in anti-reflux formulation • Critical material attribute is G and M Ratio • Alginate with high G shows stronger gel
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Typical raft components Sodium alginate •
4-8%
Precipitate in contact with gastric juice and makes a gel
Calcium carbonate •
1-3%
Calcium source for alginate gel formation; aids formation of mechanical barrier against reflux acid neutralization
•
Sodium bicarbonate •
2-4%
Makes the gel buoyant (carbon dioxide entrapped in the gel); the gel floats.
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Alginate in satiety products • Critical material attribute is G and M Ratio • Alginate with high G shows stronger gel 100
Hunger
Gap in mealtime hunger due to consumption of alginate to reduce consumed quantity
Standard Hunger Hunger with Alginate
0 0 Meal Alginate Product consumed
• •
Time
Gap in between-meal hunger to reduce snacking
Alginate product consumed before a meal reduces level of hunger at the meal, resulting in lower consumption of food After the meal, return of hunger is delayed resulting in less likely incidences of between meal snacking 24
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Alginates in controlled release matrix systems • Critical material attribute is G and M Ratio, and viscosity • Alginate with high M shows superior barrier
The pH-controlled release mechanism of alginate matrices is uniquely suited to modifying the release of highly acid soluble drugs • At low stomach pH, alginate forms an insoluble gel layer that acts as a barrier to drug diffusion, limiting release while tablet remains in the stomach • Upon passage of the dosage form into the higher pH small intestine, the alginate converts to the sodium salt form • Sodium alginate forms a soluble viscous layer that still affords a barrier to drug release by diffusion while undergoing erosion
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In vitro release of Verapamil HCl in tablets with HPMC with and without alginate HPMC (10%) (acid burst)
HPMC 9.5% and Alginate 28.4%
pH = 1.2 pH = 7.5
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Alginate viscosity provides release profile flexibility
® ®
1 hour simulated gastric fluid then simulated intestinal fluid
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Achieve 24-hour release profiles and control the effect of co-administered calcium by formulating with calcium
®
1 hour simulated gastric fluid then simulated intestinal fluid
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Batch-to-batch consistency in release profiles for Protanal® sodium alginate
® ®
1 hour simulated gastric fluid then simulated intestinal fluid
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Alginates in nano-suspension to improve solubility • Critical material attribute is G and M Ratio and Viscosity • Alginate being anionic in nature provides superior drug stabilization
Alginates exhibits superior stabilizing properties at lower concentration (20% Versus 1%)
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Alginates in solid dispersion to improve drug solubility
Drug: Lovastatin with alginates formed solid dispersion and solid solution with HPMC-AS 31
Alginates in enteric coating • Critical material attribute is G and M Ratio and viscosity
• Alginate with low viscosity and high M shows superior functionality • Alginate coating have shown effective enteric properties at the weight gain of 5-6% w/w Contour Plot of disintegration time (min) vs Glycerine, Alginate 30
disintegration time (min) < 20 20 – 40 40 – 60 60 – 80 80 – 100 > 100
Glycerine
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20
15
10 0.0
0.5
1.0 Alginate
1.5
2.0
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Alginates in enteric capsules and microencapsulation • Critical material attribute is G and M Ratio and viscosity • Alginate with high G shows superior encapsulation properties
in alginate beads 33
Alginates Chitosan Hyaluronan Validated cGMP facility in Sandvika, Norway for purification of biopolymers 34
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Ultra-pure Alginate Applications
Dermal filler Woundcare
Self-gel Bone/cartilage regeneration
Cardiovascular 35
Innovation is taking two things that already exist and putting them together in a new way. Tom Freston
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Questions!!!!
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