Alginates: The right chemistry for pharmaceutical applications

5/11/2015 Alginates: The right chemistry for pharmaceutical applications Rina Chokshi. Ph.D. Americas, Application Manager Ewing, NJ Overview • Alg...
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5/11/2015

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 70C 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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