10/11/2010

1

Pharmaceutical polymersApplication of polymers as pharmaceutical

excipients in tablets and capsules

Jyrki Heinämäki

Photo: DMV International

Content� What is a pharmaceutical excipient? Why do we need

excipients in the drug products? � What are polymers? What kind of polymers are used in

pharmaceuticals? Manufacture of polymers� Conventional applications of polymers as excipients in

tablets and capsules � Controlled-release applications of polymers:

� Oral depot pharmaceuticals� Oral enteric-coated pharmaceuticals

� Examples of some novel polymers � Quality and safety issues of pharmaceutical polymers� Literature

Ref. Jouko Yliruusi

WHAT IS A PHARMACEUTICAL EXCIPIENT?

Pharmaceutical excipients can be defined as nonactive ingredients that are mixed with therapeutically active compound(s) to form medicines. The ingredient which is not an active compound is regarded as an excipient.

- Excipients affect the behaviorand effectiveness of the drugproduct

- More and more functionality and significance

- The variability of active compound,excipients and process are obviouscomponents for the productvariability

Active compound

Excipients

Process

PRODUCT

Ref. Supplement to Pharmaceutical Technology, 2006

Excipients are commonly classified according to their application and function in the drug products:

BindersDiluents/FillersLubricantsGlidantsDisintegrants

Poolishing Film formers and coatingsagents PlasticizersColoringsSuspending agents Preservatives, antioxidants

FlavoringsSweeteners, Taste improving agentsPrinting inks Dispersing agents

CLASSIFICATION OF EXCIPIENTS

Photo: FMC Corp.

Photo: FMC Corp.

Photo: Colorcon

CHEMICAL NATURE OF EXCIPIENTS

Annex to Directive 75/318/EU. Note for guidance 3AQ9a:�Excipients in the dossier for application for marketing authorisation of medicinal product�:1. Chemical compound/excipient (e.g. organic/inorganic acids

and their salts, sugars, alcohols)2. Chemically modified excipient (e.g. cellulose derivatives)3. Mixture of chemical compounds (e.g. hydrogenated glucose

syrup)4. Ready-to-use mixture of excipients (e.g. enteric or depot

coating dispersions)5. Natural excipient6. Biological excipient of animal or human origin7. Flavoring / Artificial flavoring agents8. Coloring agent

id23278250 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com

10/11/2010

2

COMMONLY USED EXCIPIENTS IN TABLETS AND CAPSULES

� Polyvinylpyrrolidone (PVP)� Lactose

SaccharoseMicrocrystalline celluloseStarches (maize, potato)

� Magnesium stearateStearic acid, Colloidal silicon dioxide, Talc

� Sodium starch glycolate� Hypromellose (HPMC), Hydroxypropyl cellulose (HPC), Methyl

cellulose (MC), Ethyl cellulose (EC), PEGs, Titanium dioxide� Gelatin� Calcium stearate, pregelatinized maize starch, cross

carmellose, calcium phospahte, cross povidon, shellac

Reference: Mendell, A Penwest Company

WHAT ARE POLYMERS? � A polymer is a large molecule constructed from many small

structural units called monomers, covalently bonded together in any conceivable pattern / Semicrystalline structure

� When only one species of monomer is used to build a macro-molecule - homopolymer or simply polymer; if the chain are composed of two types of monomer unit, the material is known then as copolymer

� A major part of the pharmaceutical excipients are polymers or copolymers

Polymers

Natural Synthetic

ThermosettingThermoplasticElastomersGums Resins

PolysaccharidesProteins

Reference: Cowie. J.M.G., Polymers: Chemistry and Physics of Modern Materials, 2001

http://www.ims.uconn.edu

NATURAL vs. SYNTHETIC POLYMERS

I Natural polymers (e.g. celluloses, collagen, chitosan, polylactic acid)- polymers of vegetarian origin are applied in

controlled drug release systems - polymers of animal origin are applied

in wound care preparations- biocompatible, expensive to produce

and refine, batch-to-batch variability - microbiological purity

II Synthetic polymers (e.g. PVP, PVA, polymethacryl-ates)- polymers are widely and commonly applied in

various controlled drug release systems - clear advantages over natural polymers- toxicological issues should be taken into account

Chitosan

Amylose maize starch (Hylon VII)

Table 1. Examples of common polymers used as excipients in pharmaceutical tablets and hard gelatin capsulesFiller / Diluent Microcrystalline cellulose

Starches

Disintegrant StarchesCrosslinked polyvinyl pyrrolidoneSodium starch glycolateSodium carboxymethyl cellulose (NaCMC)

Binder PolyvinylpyrrolidoneCellulose derivatives (MC, HPC, HPMC)Polyethylene glycol (PEG)

Lubricant Polyethylene glycol (PEG)

Antiadherent Starches

Film coating Cellulose derivates (HPC, HPMC, HPMCP, CAP, CAT, HPMCAS, CA)Methylmethacrylate copolymersMethacrylic acid copolymersPolyvinyl acetate phthalate (PVAP)Polyethylene glycols (PEGs)

ORAL IMMEDIATE AND CONTROLLED RELEASE DRUG PRODUCTS

Immediate release (conventional) tablets/capsules are intendedto rapidly disintegrate and to release the entire drug dose (active substance) in the upper parts of the GI tract (stomach)Drug release from the oral controlled-release tablets/capsules can be either time-dependent (depot) or site-specific (enteric) products

Therapeutical and physiological aspects related to oral controlled-release dosage forms:

I Patient complianceII Improvements in drug therapy III Relatively short and variable transit time through the GI-tract IV First pass metabolismV Limited absorption of drug in the distal sections of the GI-tractVI Limitations related to size of the final drug product

ORAL DEPOT PHARMACEUTICALS

I Depot tablets / capsules- Single- and multiple units- Advantages:

- Frequency of administration- Patient compliance - Fluctuation - Adverse side effects - Costs

- Mechanism of drug release is usually diffusion or dissolution(via erosion)

- Sustained release, Prolonged release, Retarded release, Extended release, Slow release

Colorcon, 1990

10/11/2010

3

ORAL SITE-SPECIFIC (ENTERIC-COATED) DOSAGE FORMS

II Enteric pharmaceuticals- Single- and multiple units- Small intestine and/or colon- Advantages:

- Adverse side effects (irritation) - Stability of drug - Bioavailability - Local action in the intestine

- Mechanism of drug release iscommonly dissolution (via erosion)

- �Enteric release, Delayed release

Position controlled release, Colonspecific release, Colon drug delivery� Eastman Fine Chemicals, 1991

ORAL CONTROLLED RELEASE DOSAGE FORMS

Polymer

Dosage form Technology

Action- Tablets

- Capsules

- Granules/pellets

- Microcapsules

- Gels

- Protective

- Sustained release

- Site specific

- Film coating

- Matrix

- Salt formation

- Ion exchange

Degussa, 1991

DESIGN OF ORAL CONTROLLED RELEASE DOSAGE FORMS

I Dissolution controlled drug release- Matrix- Membrane (i.e. film coating)

II Diffusion controlled drug release- Matrix- Membrane (film coating)

III Ion-exchange resinsIV Osmotically controlled release (osmotic pumps)

V Floating depot productsVI Enteric and colon-specific dosage forms

DISSOLUTION CONTROLLED RELEASE

I A drug with a slow dissolution rate is inherently sustained

II Slowly erodable matrix- Carnauba wax +

stearic acid, stearyl alcohol or PEG

- Triglyserides

III Poorly water soluble, controlled release membrane (film)

Dissolution controlled release:

dm/dt = ADS / h

S= Aqueous solubility of drugA= Surface area of the dissolving

particle or tablet D= Diffusion coefficient of drugh= Thickness of the diffusion

layer

I/II III

Carnauba wax (Cera carnauba)

- Mixture of acid esters, hydroxy acids, C-H chains and water

- Leaves of Copernicia cerifera plant

- Ph.Eur., USP, JP- Mp 80-88ºC, hard wax- Practically insoluble in

water- In erodable matrices 10-

50% (m/m) either alone or combined with stearic acid, stearyl alcohol, PEGs, HPC, acryl resins, propylen glycol monostearate, and alginate/pectin

Copernicia cerifera plant

Cera carnaubahttp://www.texasdrone.com/carnauba

Insoluble matrix systemI Insoluble matrix formers:

- Ethyl cellulose- Metacrylate copoly-

mers (Eudragit®)- Vinyl polymers

(PVC, PVA/PVP)- Polyethylene- Starch acetate

II Drug and excipients are blended and compressed into a matrix tablet

III Matrix tablet may transit through the GI tract as intact or it may disintegrate as the drug has released

Diffusion controlled drugrelease:Q = [D/ (2C - S)St]1/2

Q = Amount of drug released per unit surface area

D = Diffusion coefficient = Porosity = Tortuosity of the matrix S = Solubility of drug

Kannikoski, 1990

DIFFUSION CONTROLLED RELEASE

10/11/2010

4

Ethyl cellulose (EC)

- Ethyl ether of cellulose, long chain polymer composed of -anhydro glucose units

- Ph.Eur., USP- Insoluble in water- Insoluble matrices can be

prepared by direct compres-sion technique or mixture of drug and EC can be granulated by using ethanol

Pharm.Tech.Eur., 9 (1), 26-36 (1997)

Micronized EC containing depot matrix tablet

Pharm.Tech.Eur., 9 (1), 26-36 (1997)

PVA/PVP insoluble matrix

I Insoluble and soluble matrix former (Kollidon SR):- Polyvinyl acetate 80%- Povidone (PVP) 19% - Na-lauryl sulphate andsilicon dioxide 1%

II Povidone dissolves and form porous structure, via which the drug slowly will release (diffusion)

III Dissolution of matrix is undependent on pH and ion content of the GI fluids

Basf, 2001

Compression of PVA/PVP matrix tablet

I Kollidon SR can be compressed very easily- PVA plastical

material- Povidone (PVP) acts

as a binder II Friability (hardness) of the

matrix tablet is also very good

Basf, 2001

Starch acetate as a depot matrix former Hydrophilic or gel forming matrix

I Hydrophilic matrix can be prepared from:- HPMC, HPC, MC,

NaCMC- Polyvinyl pyrrolidone

(Povidone, PVP)II Drug release is undepen-

dent on compression pressure, particle size of the drug and lubricants

III Aqueous solubility and shape of the matrix tablet affect release behaviour of the drug

IV �The hydrodynamically

balanced system, HBS�

Mainly diffusion controlled drug release; however, partly dissolutionand swelling controlled release as welldm/dt = ADS / hS = Solubility of drugA = Surface area of dissolving particle

or tabletD = Diffusion coefficient of drugH = Diffusion pathlength

Wise, Handbook of Pharmaceutical Controlled Release Technology, 2000

10/11/2010

5

Hydrophilic or gel forming matrix

Florence-Attwood, Physicochemical Principles of Pharmacy, 1998

Hydroxypropyl methylcellulose (HPMC)

- O-methylated and O-(2-hydroxypropylated) cellulose

- Ph.Eur., USP, JP- Molecular weight 10000-

1500000- Soluble in cold water and

forms viscous colloidal solution; practically insoluble in ethanol

- Application in hydrophilic matrices 10-80% (m/m)

Wise, Handbook of Pharmaceutical Controlled Release Technology, 2000

Diffusion controlled drug release system designed as film-coated tablet or granules

I Water insoluble polymeric material as a film former (and hydrophilic polymer as a core excipient)- EC- Polymethacrylates- Starch acetate*- Polyvinyl acetate

II Diffusion of drug through polymeric film (membrane) or from the matrix

III Usually drug release does not follow zero order kinetics

KalvoLa

Reservoir device:dm/dt = ADK (C/ l)

A = AreaD = Diffusion coefficientK = Partition coefficientl = Diffusional pathlengthC = Concentration difference

across the film (or membrane)

FilmDrug

Ethyl cellulose (EC)

- Ethyl ether derivative of cellulose, long chain polymer composing of -anhydro glucose units

- Ph.Eur., USP- Drug release is controlled by

diffusion through the insoluble film (membrane)

- Aqueous polymer dispersions and pseudolatexes of EC (e.g. Aquacoat ja Surelease)

- Diethyl phthalate, dibutyl sebacinate, triethyl citrate, triacetin as plasticizers

- HPMC and PEG - 3-20% film coating liquids- �Curing process�

Colorcon, 1990

Colorcon, 1990

Ethyl cellulose (EC)

Film thicknessCo-polymer Colorcon 1990

Polymethacrylates (Eudragit® NE30D and RL/RS)

- NE30D: Poly(ethylacrylate, methylmetacrylate) 2:1

- RL/RS:Poly(ethylacrylate, methyl-methacrylate, trimethyl-ammonium ethylmetha-crylate-chloride) 1:2:0.2 / 1:2:0.1

- USP- Water insoluble film

(dissolution of which is undependent on pH)

- Butylphthalate, dibutyl sebacinate, triethyl citrate, triacetin as plasticizers

- With NE30D no plasticizer is needed

- 5-20% film coating liquids- �Curing process�

Weisbrod, 2001

10/11/2010

6

Polymethacrylate (Eudragit® NE30D)

Amount of polymer

pH of dissolution medium

Weisbrod, 2001

Polymethacrylate (Eudragit® RL/RS)

Amount of polymer Polymer ratio

Anti-adhesive agentPlasticizerWeisbrod, 2001

Polymethacrylate (Eudragit® RL/RS)

�Curing time�

Weisbrod, 2001

Starch acetate

- Starch is composed of two polysaccharides (structural unit is glucose): amylose and amylopectin.

- Amylose: Linear homopoly-mer, in which polymer chain is composed of via 1-4 carbons

- Amylopectin: Branched homopolymer, in which main carbon chain is linked by 1-4 and branched is occurred via 1-6 carbons

- Starch acetate (SA) can be synthetized e.g. from maize (corn) or potato native starches

- SA is hydrophobic, DS > 1.7

Lepeniotis ja Feuer, 1997

Starch acetate films

- Aquoeus film coating form is available for sustained-release applications

- Preparation of aqueous dispersion does not require any organic solvents nor alkaline compounds (Patent FI105566, 2000)

- Potato starch acetate as a film former, in which degree of substitution (DS) > 2.8,

- Mixture of plasticizers should be applied: 2-octenyl succinic anhydride and triethyl citrate (80% polymer)

- 15-20% film coating liquids- Permeation through the

microporous film (time √-kinetics, pH undependent)

Tarvainen ym. 2004

Osmotic pump

I The tablet core is composed of drug and osmotic acitve adjuvant. The core is film coated with a semipermable coating material.

II Semipermable materials:- Cellulose-acetate- Ethyl cellulose- Polyvinyl alcohol

III �Push-Pull� �system (hole)IV Porous membrane systems

can be made by adding: - Sorbitol- PEG 400

V Severe adverse side effects (e.g. indomethacin) Osmotic pump: dm/dt = A/h(kësS)

A = Surface area of the filmk = Permeability of the filmh = Thickness of the film

Wise, Handbook of Pharmaceutical Controlled Release Technology, 2000

Wise, Handbook of Pharmaceutical Controlled Release Technology, 2000

10/11/2010

7

Cellulose acetate (CA)

- Cellulose, in which part or all OH groups are acetylated

- Ph.Eur., USP- Solubility is dependent on

the degree of acetylation. Soluble in e.g. in the mixtures of acetone and water.

- Triacetin, triethyl citrate and polyethylen glycols are plasticizers of choice

- Applicable also for effective taste masking and as adfuvant for transdermal products

Wise, Handbook of Pharmaceutical Controlled Release Technology, 2000

Ion-exchange resins

I Ion-exchange resins are water insoluble materials containing anionic or cationic groups in repeating positions

II Resins are repeatly �exposed� to drug

solutions and contaminant ions are washed and the resin is finally dried (powder)

III Drug release requires the presence of ions in solution; food and water may change ionic content of the fluids in the GI tract

Preparation and drug releasefrom the ion-exchange resins:

Preparation:[Resin � SO3Na] + DrugHCl = NaCl + [Resin - SO3.DrugH]

Drug release:[Resin� SO3DrugH] + NaCl = DrugHCL + [Resin - SO3Na]

Dowex, Amberlite andstyrene/divinyl bentzenecopolymers, in which- substituted acid groups

(cation exchange) - substituted base groups

(anion exchange)

Prolonged gastric retention

I Mucoadhesive preparations

II Floating and �heavy�

preparations

III Swellable preparations

IV Preparations with a modified geometrical shape

Mucoadhesive preparations adhere with hydrogen and electrostatic bondings to the gastric mucosa - Na-alginate, NaCMC, Alginate

acid, Polyacrylic acid, Poly-metacrylate acid

Floating and �heavy� preparations are emptied in a delayed manner from the stomach due to their product density- F: MC, HPC, HPMC,HEC,NaCMC,

Polysaccharides,Polycarbonate, Polyacrylate, Polymethacrylate

- H: Barium sulphate, Zink oxide, Titanium dioxide, Iron powder

Swellable preparations swell in the stomach so that they passage to the intestinal through the pylorus will be delayed/blocked. Do not disintegrate, different size and shape- Silastic elastomer, Polyethylene

Floating depot formulations

I Conventional gel forming, hydrodynamically balanced system (�HBS�)

II Floating depot system based on release of carbon dioxide (�Effervescent FDDS�)

J.Control.Rel., 63, 235-259, 2000

Singh ja Kim, 2000 Singh ja Kim, 2000

Summary

Florence-Attwood, Physicochemical Principles of Pharmacy, 1998

Enteric-coated drug products

I Enteric drug product resists acidic conditions in the stomach but dissolves rapidly in the intestinal tract

II Applied when the drug is acid labile or irritates the gastric mucosa

III Enteric film forming agents are commonly pH sensitive cellulose esters (polymers):- Hydroxypropyl methyl

cellulosephthalate (HPMCP)- Cellulose acetate phthalate (CAP)

- Cellulose acetate trimellitate (CAT)

- Hydroxypropyl methyl acetatesuccinate (HPMCAS)

- Polyvinyl acetate phthalate (PVAP)

Röhm Pharma, 1990

10/11/2010

8

Cellulose acetate phthalate (CAP)

- Cellulose derivative in which approximately half OH groups are acetylated and one quarter esterified with a phthalic acid

- Ph.Eur., USP, JP- Practically insoluble in water

and ethanol; soluble in acetone

- Diethyl phthalate tai triacetin can be used as a plasticizer

- Today, colloidal latex dispersion of CAP (10-30% soids) that can be diluted prior to application, is the most widely used in enteric film coating

Eastman Fine Chemicals, 1991

Cellulose acetate trimellitate (CAT)

- Cellulose in which part of the OH groups are acetylated and part are esterified with mellosic acid

- Practically insoluble in water and ethanol; soluble in e.g. acetone

- Diethyl phthalate tai triacetin can be used as a plasticizer

- Colloidal latex dispersion of CAT (10-30% soids) that can be diluted prior to application, has been developed.

- �Neutralized enteric films�

Eastman Fine Chemicals, 1991

Neutralized enteric polymer films

- Cellulose esters (e.g. CAP, CAT, HPMCP) can be modified as aqueous film formers by partially or completely neutralizing the free acid groups of the polymer

- Enteric film is formed as the coating is contacted with the acidic medium in the stomach (salt free acid groups)

- As adjuvants, triacetin (plasticizer) and magnesium carbonate (stabilizing agent) can be used

- Acid resistance and stability of the neutralized enteric film coatings can be varied

Example:CAP 8.0%Triacetin 2.0%Magnesium carbonate 0.8%Ammonium hydroxide (30%) 0.5%Purified water 88.7%

Neutralized enteric polymer films

Heinämäki ym., 1994

Neutralized enteric polymer films

Heinämäki et al.., 1994

Colon specific controlled drug release

I Colon specific drug delivery systems are applied and tested in the treatment of e.g. Crohn disease and Colitis ulcerosa as well as with dosing of insulin

II 5-amino-salicylic acid, steroids, insulin, antigeenes

III As a film former, pH-sensitive enteric films (poly methacrylate Eudragit® S and FS30D), amylose and chitosan

Eudragit® S- soluble pH > 7,0- low permeability to water

- water and organic solvents as media

- good stability

Eudragit® FS30D - new polymethacrylate for colon targeting

Pühler, 2001

10/11/2010

9

Eudragit® FS30D

Eudragit® FS30D- Poly(methylacrylate)-methyl methacrylate-co-methacrylic acid- Mol.weight 400,000 g/mol- Glass-transition temperature (Tg) 48�C- Minimum film forming temperature (MFFT) 18�C

Pühler, 2001

OTHER POLYMERS APPLIED IN CONTROLLED DRUG DELIVERY

Chitin

Insects, crustacean, shrimps,crabs etc.

Isolation

Chitin

Ref. A. Iraizoz Colarte 2004

Chitosan

Direct chain polysaccharide, readily available

Manufactured from chitin via basic deacetylation

Biodegradable, biocompatible, non-toxic

Exceptional dissolution and gel properties

Ref. A. Iraizoz Colarte 2004

Chitosan

OTHER POLYMERS IN CONTROLLED DRUG DELIVERY Chitin and chitosan

I Chitin: native (e.g. from shells of lobsters) poly-saccharide (amino polymer), which is composed of (1-4)-bonded N-acetyl-D-glucose amine units

II Chitosan: synthetized by deacetylating chitin. Mw from 50 kDa to 2000 kDa and degree of deacetyla-tion is approximately 40-98%- Biodegradable, non-toxic and stable material- Insoluble in medium pH > 7; soluble in acidic solutions

http://dalwoo.com/chitosan

I Tablets and capsulesA. Direct compression tabl.B. Binder in wet granulationC. Drug dissolutionD. Gels and emulsionsE. Film coating and capsules

( colon specific coating) F. Controlled release

matrices

II Special dosage formsF. MicroparticlesG. Bioadhesive productsH. Transmucosal deliveryI. VaccinesJ. DNA-products

A. Diluent/filler (50%) Disintegrant (> 5%) Tablet disintegrates rapidly(Crystallinity, degree of deacetylation, mw, particle size)

B. Binder capacity (-effectiveness)HPMC > Chitosan > MC > NaCMC

C. Abs. of a poorly soluble drugCo-grinding of chitosan with the active substance(e.g. griseofulvine, prednisolon)

D. Gels and emulsionsControlled release of a poorly water soluble drug (e.g. indomethacin, papaverine HCl)zero-order drug release

Chitosan as a pharmaceutical excipient Colon-specific chitosan capsules

- Oral delivery and targeting absorption of insulininsulin to colon - Chitosan capsules as a carrier system, which are film coated

using enteric hydroxypropyl methycellulose phthalate (HPMCP)

- Capsules also contained absorption enhancer for insulin and enzyme inhibitor

- Site-specific release of insulin is based on the lower pH conditions in human colon and/or activity of colon bacterial population

J.Pharm.Sci, 86, 1016-1021, 1997

10/11/2010

10

Polymer properties affecting incontrolled drug release

Polymer properties vs. diffusionInterchain forces -Segmental mobility +Molecular weight -Polymer crystallinity -Plasticizer +Copolymerization +Temperature +Glass transition -

I Diffusion in various polymer structures (diffusivity)Example: Diffusion of a drug through the film:Flux = (Area / Length) x (Permeability) x (Concentration difference)

II Solubility parameter ()Example: The drug is either dissolved or suspended in a matrix; Polymers are dissolved in a solvent and coated onto substrates

- Drug or a solvent in the system can change the strength of polymer intermolecular forces (interaction)- Cohesive energy density (CED) as a measure- (polym.) ~ (solvent)

Solubility parameter () of polymer vs. CED: = (CED)0,5

III Structure of polymerImportant parameter determining the mechanism of drug release (e.g. porosity, crystallinity, amorphous phase)

Toxicological aspects

I If the polymer to be applied in oral dosage forms, is not a new chemical entity (NCE) - A review of the manufacturer�s and published scientific literature should

be conducted to gather clinical and non-clinical safety information - Potential absorption of the polymer in the GI tract as well as local

irritations should be clarified/investigate- Toxicological studies with the finished pharmaceutical product

II If the polymer is a NCE (= new chemical entity)- The polymer material should be studied as careful and extensive as a

new active therapeutical ingredient (ATI) - In vitro and in vivo genotoxicity studies in animals

(mutagenicity, effects on cell�s DNA etc.)

- Exposure and absorption of the polymer should clarified - If the polymer is absobed a full toxicology study program is required

(acute and chronic toxicity, carcinogenicity) - If the polymer is not absorbed studies up to 6 months long are

required - Toxicology studies need to be conducted with the final formulation

Ref. http://www.amazon.com

LiteratureI Wise D.L. (toim.), Handbook of Pharmaceutical Controlled Release

Technology, Marcel Dekker Inc., New York, 890 s. (2000)p. 431-463

II Robinson J.R. ja Lee V.H. (toim.), Controlled Drug delivery, Marcel Dekker Inc., New York, 716 s. (1987)

III Chien Y.W., Novel Drug Delivery Systems, Marcel Dekker Inc., New York, 797 s. (1992)