Dedicated to Better HealthReferences: Journal of Diabetes Science and Technology 2015, Vol. 9(1) 8–16; Diabetes Technol Ther. 2017 Oct;19(10):589-594 Ideal properties State Liquid

Dedicated to

Better Health

We partner with

excellence to improve

therapies for people with

serious diseases

Eleonora Cerasoli - DDFS 2019 Berlin

Recombinant human albumin.

An effective approach for

hard-to-stabilise biologics

DDF Summit 2019

Formulation of biologics drugs is not a trivial task

Common challenges

Chemical

degradation

Oxidation

Deamidation

Truncation/degradation

Hydrolysis

.

Physical

degradation

Aggregation/fibrillation

Adsorption/depletion

Unfolding

Solubility/precipitation

~5-15% of all formulae require

“advanced”

formulation solutions

3

DDF Summit 2019

Properties and benefits of human albuminA multi-functional excipient

Albumedix recombinant human albumin - Recombumin®

Constitutes 60% of total plasma proteins

• 35-45g/L

• Increases colloidal stability of blood

Highly charged and soluble

• Net negative charge at neutral pH

• Up to 250 g/L in commercial products

High physical stability

• 17 disulphide bridges

• Stable to adverse pH and temperature conditions

Multiple hydrophobic binding sites

• Transport of heavy metals, fatty acids, toxins, hormones

• Molecular chaperone

Low immunogenicity

• Long history of safe useKnown to the human body, not a foreign compound

Support solubility

Stabiliser & Aggregation Inhibitor

Could Scavenge hydrophobic impurities

Supports chemical and structural stability

Prevents

surface - induced

aggregation

Reduces

oxidation

Minimises surface

desorption and

denaturation

Prevents

stress - induced

aggregation

Prevents

self association

4

DDF Summit 2019

Human albumin is used as a stabiliser in a range of

marketed pharmaceutical formulations


Product Company Albumin [mg/mL]

Avonex® Interferon β 1a Biogen-Idec 15

Rebif® Interferon β 1a MerckSerono 1-2

Botox® Clostridium botulinum type A toxin Allergan 0.5

Varilrix® Varicella virus vaccine GlaxoSmithKline 12.5

Monoclate-P® Factor VIII CSL Behring 15

FSME-Immun Tick borne Encephalitis Vaccine Baxter 1

ACAM2000® Smallpox Vaccine Sanofi 20

Abraxane® Paclitaxel formulated in albumin nanoparticles Celgene 45

Zevalin® Ibritumomab tituxetan Spectrum Pharmaceuticals / Bayer Healthcare 75

5

6DDF Summit 2019

Human serum albumin stabilisation against

aggregation

Mechanisms

• Multifunctional excipient

• Inhibition of aggregation across multiple

stress conditions

• Possibility to bring valuable but unstable drug

candidates to market

Dependence from buffers,

buffer components and

endogenous ligand

DDF Summit 2019

Recombumin®

Enhanced performance

No endogenous ligands

Batch-to-batch consistency

✓ Unsurpassed cGMP quality meeting USP-NF

standards

✓ Stable and assured long-term supply from reliable

manufacture

✓ Commercially validated in marketed and late-

stage clinical drug and vaccine candidates

✓ Proven acceptability by leading regulatory

agencies

✓ Expert technical and regulatory support

7

DDF Summit 2019

A wide range of application areas


Challenging peptide and protein formulations

Sub-unit vaccines formulations

Down-stream processing of viral vaccines or vectors

Biocompatible surface-coating of medical devices

Stem cell and immunotherapy

culturing

Cell therapy preservation and

formulation

8

DDF Summit 2019

Glucagon

Model peptide

Commercial formulation (Recombinant)

• Lyophilized white powder

• The reconstituted solution contains glucagon as

hydrochloride salt at 1 mg/mL (1 unit/mL)

• pH 2.5-3.5 after reconstitution - to be

administered immediately after reconstitution!

Non-Commercial Glucagon (Synthesized)

• Effect of synthesis impurities on fibrillation kinetics (*)

(*) N- and C-Terminal Hydrophobic Patches Are Involved in Fibrillation of Glucagon. Jesper

Søndergaard Pedersen, Dancho Dikov, and, and Daniel Erik Otzen, Biochemistry 2006 45 (48), 14503-14512

9

• Approved in 1960

• WHO list of essential medicines

• Hormone: increase blood sugar

levers in hypoglycaemia.

Characteristics:

• 29 amino acid (3.5 kDa)

• Extremely poor aqueous stability: soluble at pH > 9 or pH < 3

• Well characterized and known difficult peptide (poorly

soluble, physically and chemically unstable)

• Glucagon at pH 2.5 → random coil conformation, 15% helix

at the C-Terminal end.

Pdb:1BHO

DDF Summit 2019

Glucagon in dual-hormone artificial pancreasNeed of stable liquid formulation

Ideal stability for in-pump use

10

References: Journal of Diabetes Science and Technology 2015, Vol. 9(1) 8–16; Diabetes Technol Ther. 2017 Oct;19(10):589-594

Ideal properties

State Liquid

pH and isotonicity Closer to physiological

Distribution and storage Stability 24 months at 5°C and stability at 25

Pump use – Physical stability 7 days at 37°C

Pump use – Chemical stability 10 or more days > 90% at 37°C (RP-HPLC)

Aggregates of different morphology

OxidationDeamidation

Hydrolysis

DDF Summit 2019 11

StabilitySolubility

Chemical

Conformational

RP-HPLCESI-MS

SEC-HPLC

SEC-HPLCDynamic Light ScatteringThT Fluorescence

Glucagon

HSQGTFTSDYSKYLDSRRAQDFVQWLMNT

Theoretical pI: 6.75

SEC-HPLC

TSK G3000SWXL column

1 ml/min

0.1M NaCl

pH2.4-2.5

12

SolubilityH2O pH2.5

50mM Citrate-Phosphate pH5

40mM Histidine pH5

100mM Phosphate pH5

ThT Fluorescence

0.1 mg/mL Glucagon

diluted in DPBS

Thioflavin T at 0.3mM

RP-HPLC

Xbridge BEH 300 C4

0.5mL/min

A: 0.1% TFA in MQ-waterB: 0.08% TFA in acetonitrile

Stability at 40°C

pH Scouting:50mM Citrate-Phosphate pH5 - pH6 - pH7

H2O pH2.5

40mM Histidine pH540mM Histidine + Arginine40mM Histidine + Glycine

100mM Phosphate100mM Phosphate + Arginine100mM Phosphate + Glycine

Dynamic Light

Scattering

Batch Technique

SEC-HPLC: Biophysical Journal 13 Mar 2006, 90(11):4181-4194

DDF Summit 2019

Acid solution- pH2.5 and 100mM Phosphate pH5Aggregation: SEC-HPLC

Commercial Glucagon Formulation - Stabilisation at 40°C

13

DDF Summit 2019

Acid solution- pH2.5Aggregation: DLS – 2 weeks at 40⁰C

Non-Commercial Glucagon - Stabilisation at 40°C

14

No formation of ThT positive aggregates

Peak Radius (nm) %Pd %Intensity %Mass %Number

Peak 1 4.9 26 98 100 100

Peak 2 308 8.6 1.9 0 0

Peak Radius (nm) %Pd %Intensity %Mass %Number

Peak 1 1.2 20.6 19.1 99.9 100

Peak 2 13.3 17.1 6.7 0 0

Peak 3 118 33.7 72.7 0 0

Peak 4 4850 14.8 1.4 0 0

0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.25 3.5 3.75 4 4.25 4.5 4.75 5 5.25 5.5 5.75 6 6.25 6.5 6.75 7 7.25 7.5 7.75 8 8.25 8.5 8.75 9 9.25 9.5 9.75 10 10.25 10.5Retention time [min]

3x10

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

Response [m

AU

]

0.6

53

0.8

67

1.1

60

2.7

80

2.9

66

3.1

33

3.2

99

3.5

26

3.7

93

3.9

39

4.2

33

4.6

93

5.4

12

5.6

86

6.2

39

6.6

72

7.0

52

7.3

39

7.7

79

Glu

cagon

8.2

52

8.6

52

9.0

19

9.4

32

9.6

18

9.9

45

10.2

72

10.5

52

(Alb

um

in)

Shoulder sensitivity

Reset baselineShoulder sensitivity

Threshold

Width

Glucagon

Glu std W32019-02-12 10:48:54+00:00 | DAD1A,Sig=210,4 Ref=off | Glu std W32019-02-12 11-35-48+00-00-r002.dx

0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 3.6 3.8 4 4.2 4.4 4.6 4.8 5 5.2 5.4 5.6 5.8 6 6.2 6.4 6.6 6.8 7 7.2 7.4 7.6 7.8 8 8.2 8.4 8.6 8.8 9 9.2 9.4 9.6 9.8 10 10.2 10.4 10.6Retention time [min]

2x10

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2

Response [m

AU

]

2.7

80

3.5

67

4.7

13

6.2

20

6.4

33

6.6

86

6.8

93

7.0

80

7.3

13

7.9

33

Glu

cagon

8.3

33

8.4

80

9.4

13

9.5

93

9.9

26

10.2

46

10.6

26

(Alb

um

in)

GE control W32019-02-19 10:46:34+00:00 | DAD1A,Sig=210,4 Ref=off | GE control W32019-02-19 10-46-34+00-00.dx

DDF Summit 2019

Acid solution- pH2.5 Chemical degradation: RP-HPLC


15

3 Weeks incubation at 40°C

pH2.5 - no Albumin

3 Weeks incubation at 40°C

pH2.5 + Recombumin®

Cleavage products

DDF Summit 2019

Solubility Tests – Buffer scouting at pH5SEC-HPLC: Glucagon Peak Area

Non-Commercial Glucagon

16

No AlbuminRecombumin®

10mg/mLNo Albumin

Recombumin®

10mg/mL No AlbuminRecombumin®

10mg/mL

Glucagon pH2.5 50mM Citrate-Phosphate 40mM Histidine 100mM Phosphate

DDF Summit 2019

Citrate- Phosphate buffer scoutingSolutions


17

Glucagon

(mg/mL) (*)Molar Ratio(**)

pH2.5 1.02 n/a

20mg/mL Recombumin® in 50mM Citrate-Phosphate pH5 0.35 0.27



(*) Calculated by SEC-HPLC on freshly prepared solutions by using a Glucagon standard curve

(**) Glucagon/Albumin

pH scoutingAggregation: SEC-HPLC


18

Glucagon Control pH2.5

Glucagon + 20mg/mL Recombumin® in 50mM Citrate-Phosphate

DDF Summit 2019No formation of ThT positive aggregates

DDF Summit 2019

pH scoutingAggregation: Dynamic Light Scattering


19

T0

Correlograms

4 Weeks at 40°C

Correlograms

pH5, 6 and 7

Intensity Distributions

pH2.5 no albumin

pH5 + Recombumin

pH6 + Recombumin

pH7 + Recombumin

DDF Summit 2019

pH scoutingChemical Degradation: RP-HPLC


20

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.25 3.5 3.75 4 4.25 4.5 4.75 5 5.25 5.5 5.75 6 6.25 6.5 6.75 7 7.25 7.5 7.75 8 8.25 8.5 8.75 9 9.25 9.5 9.75 10 10.25Retention time [min]

3x10

0.2

0.4

0.6

0.8

1

Response [m

AU

]

0.6

53 0.8

60

1.1

53

2.7

67

2.9

40

3.1

33 3.2

87

3.5

13

3.7

80

3.9

27

4.2

27

4.6

80

5.3

87

5.6

47

6.2

00

6.6

46 7.0

26

7.3

20

7.8

00

Glu

cagon

8.2

40

8.6

06

9.0

00

9.4

13

9.6

13

9.9

26

10.2

53

(Alb

um

in)



Threshold

Width

Glucagon

Glu std GE W4 2019-02-20 19:45:55+00:00 | DAD1A,Sig=210,4 Ref=off | Glu std GE W4 2019-02-20 19-45-55+00-00-r001.dx


3x10

0.2

0.4

0.6

0.8

1

Response [m

AU

]

0.6

67

0.7

93

2.8

13

3.2

87

4.2

60

4.6

47

4.8

06

6.1

60

6.9

73

7.2

66

7.5

93

7.7

66

Glu

cagon

8.1

93

8.8

40

9.1

20

9.2

66

9.4

53

9.7

46



Threshold

Width

Glucagon

GPCP5 W4 2019-02-21 00:42:51+00:00 | DAD1A,Sig=210,4 Ref=off | GPCP5 W4 2019-02-21 00-42-51+00-00-r001.dx


3x10

0.2

0.4

0.6

0.8

1

Response [m

AU

]

0.6

60

0.9

00

2.8

13

4.2

66

4.8

06

6.2

79

6.9

73

7.5

93

7.7

46

Glu

cagon

8.1

79

8.8

46

9.1

19

9.2

66

9.4

52

9.7

46



Threshold

Width

Glucagon



3x10

0.2

0.4

0.6

0.8

1

Response [m

AU

]

0.6

60

0.7

13

0.9

93

4.1

40

4.8

07

5.6

13

6.3

20

6.9

73

7.2

47

7.6

13

7.7

73

Glu

cagon

8.1

93

8.3

40

8.6

20

8.8

67

9.1

47

9.4

73

9.7

67

10.1

40

10.3

47



Threshold

Width

Glucagon


Glucagon Control

pH2.5

Glucagon +

Recombumin

in 50mM Citrate-

Phosphate

pH5

pH6

pH7

DDF Summit 2019

pH scoutingChemical Degradation: ESI-MS


21

Glucagon Control pH 2.5

T0


1 10 20

Observed

m/z ratioIdentity

2462P21 Cleavage

(Fragment aa1-21; -1020Da)

FVQWLMNT

Glucagon Control pH 2.5

4 weeks at 40⁰C

1749P15 Cleavage

(F aa1-15; -1734Da)

SRRAQDHSQGTFTSDYSKYLDSRRAQDFVQWLMNT

1 10 20

2522P9 Cleavage

(F aa10-29; -961Da)

Glucagon + Recombumin

in 50mM Citrate-Phosphate pH5

4 Weeks at 40°C


1 10 20

DDF Summit 2019

100mM Phosphate buffer pH5 + Amino acidsSolutions


22

Glucagon

(mg/mL) (*)Molar Ratio(**)

100mM Phosphate (***) n.d. n/a

100mM Phosphate + 20mg/mL Recombumin (**) 1 0.87

100mM Phosphate + Arginine 0.27 0.48

100mM Phosphate + Arginine + 10mg/mL Recombumin 0.25 0.44

100mM Phosphate + Glycine 0.24 0.42

100mM Phosphate + Glycine + 10mg/mL Recombumin 0.24 0.43(*) Calculated by SEC-HPLC on freshly prepared solutions by using a Glucagon standard curve

(**) Glucagon/Albumin

(***)Glucagon Commercial formulation

DDF Summit 2019

100mM Phosphate buffer pH5 and Amino AcidsAggregation: SEC-HPLC

Commercial Glucagon Formulation - Stabilisation at 25°C

23

24DDF Summit 2019

100mM Phosphate buffer pH5 + ArginineAggregation: SEC-HPLC and DLS


0

20

40

60

80

100

120

0.1 1 10 100 1000

% I

nte

nsit

y

Radius (nm)

Intensity Distribution - Recombumin4 Weeks at 40⁰C

Peak Radius (nm) %Pd %Intensity

Peak 1 3.7 2.52 100

25DDF Summit 2019

100mM Phosphate buffer pH5 + ArginineChemical degradation and ThT positive fibril formation


No Albumin

+ Recombumin

RP-HPLC

Cleavage products

26DDF Summit 2019

100mM Phosphate buffer pH5 + Glycine Aggregation: SEC-HPLC and DLS


-1

9

19

29

39

49

59

69

79

89

0.1 1 10 100 1000 10000 100000 1000000

% Inte

nsity

Radius (nm)

Intensity Distribution - Recombumin4 Weeks at 40°C

Peak Radius (nm) %Pd %Intensity

Peak 1 3.9 12.34 100

No formation of ThT positive aggregates

27DDF Summit 2019

100mM Phosphate buffer pH5 + GlycineChemical degradation: RP-HPLC


100mM Phosphate pH5 + Glycine

100mM Phosphate pH5 + Glycine +

10mg/mL Recombumin®

No Albumin

+ Recombumin

Cleavage products

RP-HPLC

DDF Summit 2019

40mM Histidine pH5 + Amino acidsSolutions


28

Glucagon

(mg/mL) (*)

Glucagon/Albumin

Molar Ratio

pH2.5 1 1.9

40mM Histidine 0.4 0.8

40mM Histidine + 10mg/mL Recombumin 0.3 0.6

40mM Histidine + Arginine 0.7 1.3

40mM Histidine + Arginine + 10mg/mL Recombumin 0.4 0.8

40mM Histidine + Glycine 0.4 0.7

40mM Histidine + Glycine + 10mg/mL Recombumin 0.4 0.7

(*) Calculated by SEC-HPLC on freshly prepared solutions by using a Glucagon standard curve

DDF Summit 2019

40mM Histidine pH5 + Amino acidsAggregation: DLS


29

Histidine pH5 + Arginine

Histidine pH5 + Arginine +

Recombumin

1

1.2

1.4

1.6

1.8

2

2.2

1 100 10000 1000000

Inte

nsity

Auto

corr

ela

tion

Time (µs)

+ 20mg/mL Arginine4 Weeks at 40⁰C

1

1.2

1.4

1.6

1.8

2

2.2

1 100 10000 1000000

Inte

nsity

Auto

corr

ela

tion

Time (µs)

+ 20mg/mL Glycine4 Weeks at 40⁰C

40mM Histidine pH5 alone or plus Arginine or Glycine

40mM Histidine pH5, 10mg/mL Recombumin® alone or plus Arginine or Glycine

1

1.2

1.4

1.6

1.8

2

2.2

1 100 10000 1000000

Inte

nsity

Auto

corr

ela

tion

Time (µs)

Only buffer3 Weeks at 40⁰C

0

10

20

30

40

50

60

70

0.1 10 1000 100000

% Inte

nsity

Radius (nm)

Histidine buffer3 Weeks at 40°C

0

10

20

30

40

50

60

70

80

90

100

0.1 10 1000 100000

% Inte

nsity

Radius (nm)

Histidine buffer + Arginine4 Weeks at 40°C

-1

19

39

59

79

99

119

0.1 10 1000 100000

% Inte

nsity

Radius (nm)

Histidine buffer + Glycine4 Weeks at 40°C

DDF Summit 2019

40mM Histidine pH5 + Amino acidsAggregation: ThT fluorescence


30

Recombumin® Samples

DDF Summit 2019

40mM Histidine pH5 + Amino acidsChemical Degradation


31

pH2.5

40mM Histidine pH5 alone or plus Arginine or Glycine

40mM Histidine pH5, 10mg/mL Recombumin® alone or plus Arginine or Glycine

0

20

40

60

80

100

120

0 10 20 30

% R

ecovery

Time (Days)

Histidine pH5

0

20

40

60

80

100

120

0 10 20 30

% R

ecovery

Time (Days)

Histidine pH5 + Arginine

0

20

40

60

80

100

120

0 10 20 30

% R

ecovery

Time (Days)

Histidine pH5 + Glycine

32

Accelerated stability studies results

Summary

No Albumin with Recombumin®

SEC-HPLC RP-HPLC ThT Assay DLS SEC-HPLC RP-HPLC ThT Assay DLS

H2O pH2.5 (*) 4 weeks

50mM Citrate-Phosphate pH5 not tested not tested not tested not tested



100mM Phosphate pH5 (**) not tested not tested not tested not tested not tested not tested

100mM Phosphate pH5 + Arginine

100mM Phosphate pH5 + Glycine

40mM Histidine pH5 not tested not tested

40mM Histidine pH5 + Arginine not tested not tested

40mM Histidine pH5 + Glycine

(**) Commercial formulation

DDF Summit 2019

A wide range of application areas


Challenging peptide and protein formulations

Sub-unit vaccines formulations

Down-stream processing of viral vaccines or vectors

Biocompatible surface-coating of medical devices

Stem cell and immunotherapy

culturing

Cell therapy preservation and

formulation

33

Booth N⁰6

Aggregates of different morphology

DDF Summit 2019 35

StabilitySolubility

Chemical

Conformational

Glucagon

Surface Adsorption

• Loss of API• Surface induced conformational

change and aggregation

36DDF Summit 2019

Recombumin®- coated dialysis cassette

Commercial Formulation - Adsorption experiment

Preparation Incubation Analysis

Acidic water, pH2.5

Reconstituted glucagon

in dialysis cassette

(no Recombumin®)

Reconstituted glucagon

in Recombumin® -

coated dialysis cassette

Rt, 2 hours

Peptide recovery

monitored

by UV absorbance (280nm)

or

37

Recombumin® significantly improves peptide

recovery

Commercial Formulation - Pre-treatment of surfaces with Recombumin®

In-use applications

During production and recovery process

• Chromatography

• Filtering

• Pumping

• Pipes and tubes

During storage and in-use

• Vials and stoppers

• Injection and infusion devices

Recovery of glucagon after dialysis

http://www.google.dk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.bioprocessintl.com/2014/recovery-purification/&ei=SvVRVZ2_GMONsAGj54GoCQ&bvm=bv.92885102,d.bGg&psig=AFQjCNFWRfJbTpdn43TbmOHptNr4fC4rLw&ust=1431520954975450

DDF Summit 2019

Scouting of different buffers at pH5Aggregation: SEC-HPLC

Commercial Formulation - Stabilisation at 25°C

38

0

5

10

15

20

25

0 20 40 60 80 100 120

Are

a (

mA

U*m

in )

Time (h)

Glucagon 0.98mg/mL, 100mM PB pH 5

Glucagon 0.98mg/mL, 100mM PB pH 5,20mg/mL Recombumin

Glucagon 0.98mg/mL, 100mM Citrate pH 5,20mg/mL Recombumin

Glucagon 0.98mg/mL, 40mM Histidine pH 5,20mg/mL Recombumin

Histidine > PB >Citrate

DDF Summit 2019

Recombumin® and HSA comparison:

aggregates

Reproducible product quality

Recombumin®: highly monodisperse. Present a single species with RH between 3.4 - 4.4nm (depending on the

concentration).

0

20

40

60

80

100

0.05 0.5 5 50 500

% Inte

nsity

RH (nm)

Dynamic Light Scattering Intensity Distribution

AlbIX 1:1

Recombumin®

HSA

39

DDF Summit 2019

… but try not to use such a low pH!

pH2.5 is not good for a protein

40

4.6 4.8 5 5.2 5.4 5.6 5.8 6 6.2 6.4 6.6 6.8 7 7.2 7.4 7.6 7.8 8 8.2 8.4 8.6 8.8 9 9.2 9.4 9.6 9.8 10 10.2 10.4 10.6 10.8 11 11.2 11.4 11.6 11.8 12 12.2 12.4 12.6 12.8 13 13.2 13.4 13.6 13.8 14 14.2 14.4Retention time [min]

2x10

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

2

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9

3

3.1

3.2

3.3

3.4

Response [m

AU

]

6.1

16

7.9

62

8.5

16

Monom

er

9.7

12

11.0

22

12.9

19

14.0

95

(Poly

mer)

(Trim

er)

6.7

23 *

Trim

er

8.5

43 *

Monom

er

12.4

59 *

Glu

cagon

14.3

59 *

7.2

52

Dim

er

8.5

05

Monom

er

12.4

31

Glu

cagon

Integration off


MonomerDimerTrimerPolymer Glucagon

GE W3 control2019-02-19 09:56:25+00:00 | MWD1A,Sig=280,4 Ref=off C1 D02019-01-30 12:11:49+00:00 | MWD1A,Sig=280,4 Ref=off Stab1-C1-W22019-02-13 13:10:19+00:00 | MWD1A,Sig=280,4 Ref=off

Dedicated to Better HealthReferences: Journal of Diabetes Science and Technology 2015, Vol. 9(1) 8–16; Diabetes Technol Ther. 2017 Oct;19(10):589-594 Ideal properties State Liquid

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