5/11/2015

1

Alginates: The right chemistry for pharmaceutical applications

Rina Chokshi. Ph.D. Americas, Application ManagerEwing, 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

5/11/2015

2

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 hyperboreaLaminaria japonicaLessonia trabeculataLessonia nigrescensDurvillaea antarctica

Laminaria hyperborea

Lessonia nigrescens

Laminaria japonica

Durvillaea antarctica

Lessonia trabeculata

4

5/11/2015

3

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. 150-160.000 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

Harvesting0,3 %

Storms12 %

Total resources 50 mill MT

Sustainability in harvesting

5

Alginate is a structural building unit in brown seaweedsFunctionality is determined by chemical composition

Alginate is a natural polysaccharide; biocompatible, biodegradable, and safe for consumption (GRAS, E400-405)

Chemical composition

6

5/11/2015

4

Chemical composition of alginate: 2 Monomers

Na+

OHO

OO

HO

-OOC

(1,4) ß-D-mannuronate

O

OHO

O

OH

-OOC

(1, 4) -L-guluronate

Na+

(M monomer)

(G monomer)

7

Chemical composition of alginate: 3 Block types

O OC

O

OOHO

HO-OOC

OO

HO

HO-OOC

MO H

OH

O

O

O H O HO

O

O

-OOC

HOO

OHOO

O

-OOC

HO

M M MOH

CO O-M

G

O

CO O- C OO -

OH

O

O

OH

O

OH

O O

O

OH

G G G G

C OO-

O H O H

O H O H

C O O -

O

O

-

G-Block

M-Block

Alternatingor mixed block

8

5/11/2015

5

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

OH O

OOH O

-O O C

O

O H

O

O

O H-O O C

( 1 4 ) -D - m a n n u r o n a te

( 1 4 ) - L - g u lu r o n a te

9

Alginic acid

Na2CO3

K2CO3

NH4CO3

MgCO3

CaCO3

Propyleneoxide

Na-alginate*

K-alginate*

NH4 –alginate*

Mg-alginate*

Ca-alginate

Propylene glycolalginate*

WASHING/GRINDING

Other salts

Alginates with special functional properties

INCORPORATION

ALGINIC ACID

PRECIPITATION

EXTRACTION

SCREENING/FILTERING

DRYING/MILLING

FILLING/PACKING

QUALITY CONTROL

BLENDING

SHIPPING

Manufacturing process and salt incorporation

*) Water soluble salts

Protacid

SEAWEED RAW MATERIAL

Incorporation/neutralization is one key step in manufacturing process determining properties of final product;

10

5/11/2015

6

Various alginate grades available for applications

Products G /M ratioViscosity at 1% solution

cpsParticle 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

11

Alginate provides two basic functionalities

Thickeningi.e., viscosity,stabilization

…and Gelling This gel contains less than 1% alginate and almost 99% water

12

5/11/2015

7

Alginates: Critical material attributes

Material Attribute

Alginate compositi

on G:M ratio

Viscosity

Molecular weight

Concentration

Particle size

13

0

5000

10000

15000

20000

25000

30000

0.0 1.0 2.0 3.0 4.0

High Medium Low

Concentration (%)Rule of thumb:

* Double alginate concentration increases viscosity 8-10 times

* Double viscosity by increasing concentration 20%

Vis

cosi

ty (m

Pa.s

)

Typical viscosity grades

Viscosity of alginates at different concentrations

14

5/11/2015

8

0100200300400500600700800900

0 10 20 30 40 50 60

HighMediumLow

Temperature (oC)

Vis

cosi

ty (m

Pa.s

)

Viscosities of 1.0% concentration at different temperatures

Viscosity of alginates at different temperatures

Typical viscosity grades

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 thestructure‐function relationships in native and structurally engineeredalginates. 2008, Norwegian University of Science and Technology, Faculty ofNatural Sciences and Technology, Department of Biotechnology: Trondheim.

16

5/11/2015

9

Controlled gel formationStage 1: Disperse and hydrate alginate

Rule of thumb:* Assist dispersion by dry-blending with other powders or slurrying in oil * Sequestrant necessary unless calcium low or temperature above 70C

Alginate powderSequestrant

Ca2+

Hydrated alginateSodium alginate solution

High shear mixing

17

Controlled gel formationStage 2: Control calcium release for gelation

Hydrated alginateSodium alginate solution Alginate gel

Calcium alginate gel

Calcium salt Ca2+

Sequestrant

Ca2+ MoreCa2+

18

5/11/2015

10

Alginate applications

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, …

Technical/Industrial• 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); Raft-forming component in Acidex (Pinewood) TUMS (GSK), Maalox (Sanofi Aventis), Algicon and Algicote (Aventis) ,

Sustained ReleaseIsoptin/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 careKaltostat (Convatec), ReliaMed (AMS), Coalgan (Brothier), NuDerm (J&J), AlgiSite (S+N), Tegagen (3M),

20

5/11/2015

11

Alginates in pharmaceutical applications

21

Alginates applications

Anti reflux

Satiety application

Controlled release

Nano-suspension and Solid dispersion

Enteric coating

In-situ gel formation

Targeted drug

delivery

Biomedical application

Active ingredient

Alginates in anti-reflux formulation

22

• Critical material attribute is G and M Ratio• Alginate with high G shows stronger gel

5/11/2015

12

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.

23

0

100

0

Time

Hu

ng

er Standard Hunger

Hunger with Alginate

Alginate in satiety products

• 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

Alginate Product consumed

Meal

Gap in mealtime hunger due to consumption of alginate to reduce consumed quantity

Gap in between-meal hunger to reduce snacking

• Critical material attribute is G and M Ratio• Alginate with high G shows stronger gel

24

5/11/2015

13

Alginates in controlled release matrix systems

25

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

• Critical material attribute is G and M Ratio, and viscosity • Alginate with high M shows superior barrier

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%

26

pH = 1.2pH = 7.5

5/11/2015

14

Alginate viscosity provides release profile flexibility

®

®

1 hour simulated gastric fluid then simulated intestinal fluid

27

®

1 hour simulated gastric fluid then simulated intestinal fluid

Achieve 24-hour release profiles and control the effect of co-administered calcium by formulating with calcium

28

5/11/2015

15

Batch-to-batch consistency in release profilesfor Protanal® sodium alginate

®

®

1 hour simulated gastric fluid then simulated intestinal fluid

29

Alginates in nano-suspension to improve solubility

30

Alginates exhibits superior stabilizing properties at lower concentration (20% Versus 1%)

• Critical material attribute is G and M Ratio and Viscosity • Alginate being anionic in nature provides superior drug stabilization

5/11/2015

16

Alginates in solid dispersion to improve drug solubility

31

Drug: Lovastatin with alginates formed solid dispersion and solid solution with HPMC-AS

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

32

Alginate

Gly

ceri

ne

2.01.51.00.50.0

30

25

20

15

10

> – – – – < 20

20 4040 6060 8080 100

100

time (min)disintegration

Contour Plot of disintegration time (min) vs Glycerine, Alginate

5/11/2015

17

Alginates in enteric capsules and microencapsulation

in alginate beads

33

• Critical material attribute is G and M Ratio and viscosity• Alginate with high G shows superior encapsulation properties

Validated cGMP facility in Sandvika, Norway for purification of biopolymers

AlginatesAlginates

ChitosanChitosan

HyaluronanHyaluronan

34

5/11/2015

18

Ultra-pure Alginate Applications

Dermal fillerDermal filler

Self-gelSelf-gel

WoundcareWoundcare

Bone/cartilage regeneration

Bone/cartilage regeneration CardiovascularCardiovascular35

Innovation is taking two things that already exist and putting them together in a new way.

Tom Freston

36

5/11/2015

19

Questions!!!!

37