4 Formulation of Biotech Products - Xidianweb.xidian.edu.cn/yqxia/files/20140222_213312.pdf · 2014-02-22 · Outline 3 Excipients in parenteral formulations Delivery of proteins

By Yuqiong Xia2014

Formulation of Biotech Products

Pharmaceutical Biotechnology

Keywords

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Formulation, expicients, parenteral, solubility, anti-, adsorption, preservative, antioxidiant, osmotic pressure

Administration, IV, SC, IM, IP, Pulmonary, nasal Biodegradable microspheres, self-regulating mAb, immunoconjugate

生物制药工程夏玉琼西安电子科技大学

Outline

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Excipients in parenteral formulations Delivery of proteins Routes of administration Absorption enhancement Carrier system in rate-controlled delivery Carrier system in site-specific delivery


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Components in marketed formulations生物制药工程夏玉琼西安电子科技大学

Solubility enhancers

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Amino acids such as lysine and arginine Surfactants such as SDS

Solubility increase with higher arginine concentration


Protein adsorption and aggregation

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Protein can be adsorbed to the interface like water/air, water/container wall and water/needle

Adsorbed proteins form aggregates and precipitate


Anti-adsorption and anti-aggregation agents

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1% Albumin (白蛋白) Adsorb to surfaces instead of drugs

Surfactant Adsorb to the hydrophobic interfaces Turn the interface hydrophilic


Buffer components

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Phosphate, citrate and acetate buffer Short, temporary pH change can cause

aggregation

http://3.imimg.com/data3/CA/NX/MY-5149559/buffer-solution-250x250.jpg


Preservatives (防腐剂) and antioxidants

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Antioxidants belong to preservatives Easily oxidized amino acids Methionine, cysteine, tryptophan, tyrosine, histidine

Inert gas in the vials can reduce oxidation


Antioxidants

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Ascorbic acid (抗坏血酸，维生素C)

Acetylcysteine （乙酰半胱氨酸）

http://www.medicalook.com/molecular/ascorbic_acid.gifhttp://ts1.mm.bing.net/th?id=H.4941541510548252&pid=1.7


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Lyoprotectants Let proteins keep structures during freeze-drying Glycol

Cake formers Help to form tablet

Lyoprotectants/cake formers生物制药工程夏玉琼西安电子科技大学

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Freeze-drying

http://www.food-manufacturer.com/faqs/freeze-dried-knowledge/freeze-drying-process.html

Blue circles: Water molecules

dry dry rehydrate


Osmotic agents

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Adjust the osmotic pressure Saline and mono- or disaccharide solutions

http://chemistry2.csudh.edu/rpendarvis/monosacch.html


Outline

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Parenteral route

http://biology-forums.com/index.php?action=gallery;sa=view;id=8179

IM SC IV


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Intraperitoneal (IP 腹腔) injections

http://ehs.uc.edu/lams/data/ratsmice/9040/40_030.html


Blood half-life (t1/2) of drugs using parenteral route

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t-PA, a few minutes Monoclonal antibody (mAb), a few days IV Versus IM and SC Proteins using IV have shorter half-life Proteins using IV have more degradation reactions

and different deposition


Oral route

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Patient friendly Low bioavailability Protein degradation in the gastrointestinal (GI) tract Poor permeability of the wall of the GI tract

http://www.uofmmedicalcenter.org/healthlibrary/Article/40233


Oral route is suitable for vaccine

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To elicit an immune response, a little vaccine to target site is enough


Nasal administration

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Only work for the nose Low bioavailability if systemic action is required

http://www.emsworld.com/article/10251608/intranasal-drug-administration


Pulmonary（肺的）route

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Moderate bioavailability Patient friendly Fast uptake (faster than SC)

http://waleedtaha.tripod.com/rdds/


Outline

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Absorption enhancer in nasal administration

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Glycocholate (甘胆酸盐)

胰高血糖素

降血钙素

胰岛素

人生长激素


Absorption enhancer in nasal administration

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Starch microsheres

1 empty starch microspheres2 soluble insulin 2.0 IU/kg3 soluble insulin IV 0.25 IU/kg4 insulin in starch microsphere 0.75 IU/kg5 insulin in starch microshphere 1.75 IU/kg


Absorption enhancing using iontophoresis

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Transdermal iontophoretic delivery 离子电渗疗法

pH = 4 or 9

pH = 7.3


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Absorption enhancing using iontophoresis

Yellow: IV 10 mg/kg; 0.025 mg/mlBlue: SC, 10 mg/kg; 0.025 mg/mlRed: iontophoresis, (1 mg/g; 0.17 mA/cm2; 5cm2 patch)


Outline

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PEGylation in rate-controlled delivery

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Polyoxyethylne glycol (PEG) attachment to proteins

PEG-UK has longer half-life

PEG-UK is more efficient

UK 尿激酶，治疗血栓

PT 凝血酶原时间，表征血栓


Carrier system in rate-controlled delivery

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Open loop system Mechanical pumps Osmotically driven systems Biodegradable microspheres

Closed loop system Biosensor-pump combinations Self-regulating systems Encapsulated secretory cells


Open loop systems: mechanical pumps

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Energy failure, problems with syringe, accidental needle withdrawal, leakage of catheter（导管） and problem with injection site

Problem with long-term drug stability The patient has to adapt to the pump rate http://www.cwladis.com/math104/bolus.jpg


Osmotically driven systems

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Subcutaneously implantable, osmotic mini-pump Fixed rate

Semi-permeable membrane

Drug solution leaving via delivery portal

Flow moderator

Water entering

Drug reservoir


Biodegradable microspheres

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PLGA （聚乳酸-聚羟基乙酸） microspheres prolonged the dosing interval of LHRH agonists from 1~3 months to 6 months

http://polyscitech.com/PLGA/PLGA.png


Biodegradable microspheres

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Dextran（葡聚糖）-based microspheres

http://0.tqn.com/d/chemistry/1/0/s/E/1/Dextran.jpg

Dextran microspheres prolonged the release time of IgG from 10~ days to 20+ days


Closed loop systems: biosensor-pump combinations

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A biosensor Measure the plasma level of the protein

An algorithm Calculate the required input rate

A pump system Administrate the drug at the required rate


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Biosensor-pump combinations生物制药工程夏玉琼西安电子科技大学

Self-regulating systems

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Insulin release as a function of glucose concentration By competitive desorption By enzyme-substrate reaction


By competitive desorption

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Con A with glycosylated insulin is administrated

ConA can bind to glucose more stronger than glycosylated insulin


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Results of the above insulin delivery

Dogs with pancreatic problems

▲Dogs with pancreatic problems after insulin delivery○Normal dogs


By Enzyme-substrate reactions

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Acid sensitive polymers, enzyme and insulin Enzyme catalyzes glucose to gluconic acid pH becomes low Acid-sensitive polymers release insulin

http://ts1.mm.bing.net/th?id=H.4516021944648358&pid=1.7http://ts4.mm.bing.net/th?id=H.4696088444078218&pid=1.7

enzyme

Glucose Gluconic acid


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Encapsulated secretory cells (implanted)生物制药工程夏玉琼西安电子科技大学

Outline

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Site-specific delivery

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Maximize therapeutic effect Avoid toxic effects

http://www.pharmainfo.net/santosh-kumar-jh/site-specific-targetting


Carrier system in site-specific delivery

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Passive targeting Particles up to 100 nm can enter leaky tumor tissues,

but not compact normal tissues

Active targeting An active moiety A carrier A homing device


“natural targeting devices”: antibody

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Fc activates complement Complement causes lysis of target cells


Murine mAb as carrier

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Produce human anti-mouse antibody (HAMA) To avoid HAMA Use F(ab)2 or F(ab) fragments Use human Fc part and murine Fab part Use completely human MAb in transgenic mouse


Bispecific antibodies

46http://www.whatisbiotechnology.org/assets/exhibitions/milstein/milstein-clinical-m5.png

Bispecific antibody brings target cells or tissuets to effector cells and trigger cytotoxity

Target cells or tissues Bind to effector cells

Bispecific antibody


Immunoconjugates

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Conjugate drug to antibody

D: drugs


Summary

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Excipients in parenteral formulation Routes of administration: IV, IM, SC, IP, oral, nasal,

Pulmonary Absorption enhancement in nasal route Carrier system in rate-controlled delivery:

PEGylation, biodegradable microshpere Carrier system in site-specific delivery: mAb,

biospecific antibody, immunoconjugate


Homework 3 (choose one)

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Classify the excipients in Insulin Aspart Injection: glycerol, phenol, ZnCl2, Na2HPO4, NaCl, HCl/NaOH, steril water

Classify the excipients in EPO (促红细胞生成素) injection: human albumin, NaCl, sodium citriate, trisodium citrate


Documents

4 Formulation of Biotech Products - Xidianweb.xidian.edu.cn/yqxia/files/20140222_213312.pdf · 2014-02-22 · Outline 3 Excipients in parenteral formulations Delivery of proteins