P ol ymer M em b r a nes in Drug Deliver y Appli c a tions

Riyasudheen N. Polymer Science and Technology Laboratory NIT Calicut

 Membranes are used in drug delivery, artificial organs,

tissue regeneration, diagnostic devices, as coatings for medical devices, bioseparations, etc.
The total membrane area produced for medical

applications almost matches all industrial membrane applications together

Only in the US for example, the medical membrane

market approaches 1.5 billion dollars per year and grows steadily.

Biomaterials
Substances in therapeutic or diagnostic systems that are in contact with biological fluids

Biocompatibility
Blacks definition the biological performance of a certain material in a specific application and its acceptance/ suitability for such application if both host and material responses are optimal

Biodegradability

Blood compatibility
Incompatibility brings,

reduced coagulation platelet adhesion protein adsorption hemolysis ,etc.. Also, flux decline and lowered membrane selectivity (fouling) caused mainly by protein adsorption.

Bioresorbable polymers
Bioresorbable materials degrade products that are normal metabolites of the body.
eg: polylactide, polyglycolide, polycaprolactone and polyhyaluronic acid esters, but also natural polymers like collagen, chitosan.

Drug delivery
The goal of an ideal drug delivery system is to deliver a drug to a specific site, in specific time and release pattern. The constant drug level in blood or sustained drug release to avoid multiple doses and bypassing of the hepatic first-pass metabolism are the main challenges for every delivery system

Why do we need controlled drug delivery?

Disadvantages of current methods

The traditional medical forms (tablets, injection solutions, etc.) provide drug delivery with peaks, often above the required dose
The drug does not reach the active site
wasteful, potential toxic responses at other sites

The drug does not reach the active site in the desired concentration
expensive, ineffective at applied dose

Advantages of new methods

Maintenance of drug levels within a desired range
efficient, need for fewer administrations

Delivery of difficult drugs

slow release of water-soluble drugs, fast release of low-solubility drugs

 Two types of membrane systems for drug delivery

1. Osmotic membrane systems.

Recently, cellulose acetate asymmetric membrane capsules have been developed for osmotic delivery

A.G. Thombre, J.R. Cardinal, A.R. DeNoto, D.C. Gibbes, Asymmetric membrane capsules for osmotic drug delivery II. In vitro and in vivo drug release performance, J. Controll. Release 57 (1) (1999) 65.

Diffusion controlled membrane systems

The transport is dependent on the drug diffusivity through the membrane and the thickness of the membrane, according to Ficks law. The membrane can be porous or non-porous and biodegradable or not.
Fick's First Law

J -Flux c/ x-Conc.gradient D -Diffusion Coefficient.

Fick's Second Law

Correlation of permeabilities of steroids in various polymers with steroid melting temperature

A.S. Michaels, P.S.L. Wong, R. Prather, R.M. Gale, A thermodynamic method of predicting the transport of steroids in polymer matrices, AIChE J. 21 (6) (1995) 10731080.

Pills
The diffusion principle is applied to pills and tablets. The drug is pressed into tablet which is coated with a non-digestible hydrophilic membrane. Once this membrane gets hydrated, a viscous gel barrier is formed, through which the drug slowly diffuses. The release rate of the drug is determined by the type of membrane used

Implants
Implants consist of a membrane reservoir containing a drug in liquid or powder form. The drug slowly diffuses through the semi-permeable membrane and the rate of diffusion depends on the characteristics of both the drug and membrane. The thickness of the membrane is constant to secure uniformity of drug delivery. If the membrane degrades, drug delivery should be accomplished prior to membrane degradation. If the membrane is made of nondegradable material, it should be surgically removed afterwards. A drawback of implants is the risk of membrane rupture resulting in drug-dumping: a sudden release of large amounts of drugs.

Patches
Schematic illustration of ocular device.

Eg:are ocular (eye) and transdermal Ocular patches are typical membrane-controlled reservoir systems. The drug, accompanied by carriers, is captured in a thin layer between two transparent, polymer membranes, which control the rate of the drug release . Through diffusion, the drug is directly administered to the target area. In transdermal drug delivery (TDD), the drug is incorporated into a patch and delivered through the skin either due to the concentration difference or other driving forces (e.g. electrical current).

Polymersomes
Self assembled polymer shells composed of block

copolymer amphiphiles used for encapsulation of

biofunctional compounds and subsequent their release.
Especially,

biodegradable polymersomes can be potentially used for target

delivery to specific sites of the body . Meng et al.encapsulated the model compound carboxy fluorescein (CF) into polymersomes of amphiphilic copolymers based on polyethylene glycol (PEG) and biodegradable polyesters or polycarbonate. The release of CF at room temperature and 60 C followed first order kinetics confirming a membranecontrolled reservoir system.

Transdermal drug delivery

Skin is the largest organ of the human body (approx. 2m2 of surface area) and is a complicated multilayer organ.

Drugs can potentially pass through the skin either via the intact SC and/or via hair follicles and sweat ducts .

Passive diffusion
The most popular TDD systems are based on passive drug delivery. In these systems, drug delivery through skin is due to the drug concentration difference between the patch and the skin. Technologies developed to provide controlled passive drug delivery can be classified into two main categories.

1. Membrane or reservoir systems. 2. Matrix systems.

Membrane or reservoir systems.

Drug release can be controlled by varying the reservoir composition, drug permeability through the membrane (by tailoringthe material, porosity or thickness) and/or through the adhesive layer.

Matrix systems.
The drug is incorporated (dissolved and/or distributed) into a polymer matrix . There is no membrane and the adhesive layer is added when the matrix itself is not adhesive.

 The major parts of TDD systems such as the impermeable layer, the reservoir, the pressure adhesive layer, the membrane are all prepared from polymers.

The range of the polymers used is broad;

1. natural polymers (gelatin, starch, etc.), 2. semisynthetic (hydroxylpropyl cellulose, nitrocellulose, cellulosic, etc.), 3. synthetic (polysiloxane, polybutadiene, polyisoprene, silicone rubber, polyesters, polyurethane, polyethylene vinyl acetate, polyacrylamide, polyvinyl alcohol, polysulfone, polymethyl methacrylate, etc.)

The drug delivery through the skin due to the drug concentration difference between the patch reservoir (CD,res) and the skin (CD,skin) can be described by Ficks law:

JPD D is the steady state drug flux through the skin, kD is the drug partition coefficient in the skin, DD is the diffusion coefficient of the drug through the skin and is the skin thickness. When CD,res>>CD,skin, then : K PD D is the passive drug permeability coefficient through the skin.

Skin or device controlled delivery Total permeability (KD,total) of the drug through the membrane and skin is given by:

KD,memb, KD,skin represent the permeability of the drug through the membrane and the skin, respectively. Delivery may be primarily,
skin-rate controlled If, ratio KD,memb/KD,skin < 0.2 membrane controlled If, ratio KD,memb/KD,skin > 5

To ensure that the drug delivery is invariant of the patient or patch position, the delivery rate should be membrane controlled.

Some examples of commercial passive TDD systems

Trade name Nitroderm Nitrodur Frandol-Tape Company Alza/Ciba Key/Schering Nitto Electric Ind. Type Reservoir Matrix Matrix Drug Nitroglycerin Nitroglycerin Isosorbide dinitrate Action Anti-anginal Anti-anginal Anti-anginal

Catapres
Duragesic TransdermScop Estraderm Minitran

Alza/Boehringer Ing.

Reservoir

Clonidine
Fentanyl Scoparamine Estradiol Glyceryl trinitrate

Antihypertensive
Narcotic analgesic Anti-motion sickness Hormonal Anti-anginal

Alza/Ivers/Jansen Reservoir Alza/Ciba Alza/Ciba 3M Reservoir Reservoir Reservoir

Bio-artificial polymer membranes

Combining the characteristics of synthetic polymers with biopolymers Synthetic polymers- polyvinyl alcohol (PVA), polyacrylic
acid (PAA), poly(ethylene-co-vinyl alcohol) (EVAL), poly(acrylonitrileco-acrylic acid) (P(AN-AA)), poly(N-isopropylacrylamide) (PNIPAM) etc.

Biological polymers- fibrin, collagen, hyaluronic acid

(HA), gelatin, dextran (Dex), chitosan, starch.

Smart polymer membranes

Responsive polymers that are affected by external stimuli (e.g., temperature, pH, .) The deposition of intelligent polymers onto the surfaces of membrane pores can create permeation switches or gates.
Smart polymer membranes

Temperature Sensitive membranes

(PNIPAAm), one of the most widely studied stimuliresponsive polymers that changes its molecular chain conformation in response to temperature in aqueous environments. It exhibits a lower critical solution temperature of approximately 32 C in aqueous solution, below which the polymer is hydrophilic and above which they become hydrophobic. Temperature Sensitivity:
Set Critical Solution Temperature(LCST) Stable Below LCST Deform and release drugs when above LCST Release triggered by body temperature

Thermo-responsive release of core-shell microcapsules

Liang-Yin Chu, Sang-Hoon Park, Takeo Yamaguchi and Shin-ichi Nakao, Preparation of thermo responsive core-shell microcapsules with a porous membrane and poly(N-isopropylacrylamide) gates Journal of Membrane Science 192 (2001) 2739

H-bonding between amidewater (hydration) and amideamide (dehydration)

Construction of comb-like poly(N-isopropylacrylamide) layers on microporous polypropylene membrane

Schematic representation for the coupling of 2-bromoisobutyryl bromide to the poly(HEMA) layers and surface-initiated ATRP of NIPAM.

Ling-ShuWan, Yun-Feng Yang, Jing Tian, Meng-Xin Hu and Zhi-Kang Xu, Construction of comb-like poly(N isopropylacrylamide) layers on microporous polypropylene membrane by surface-initiated atom transfer radical polymerization, Journal of Membrane Science 327 (2009) 174181

PH Sensitive polymer membranes

pH Sensitive polypropylene porous membrane prepared by grafting acrylic acid in supercritical carbon dioxide The conformation of the PAA chains changes from coiled at lower pH to more stretch at higher pH. The stretched conformation will plug the pores partly or even completely provided that the grafted chains are enough and/or longer enough, which results in the decrease in the active pore size, pH Sensitivity:
LCST sensitive to pH LCST increases with increasing pH Deform and release drugs when above LCST Release triggered by body pH environment

pH dependence of virgin PP membrane (a) and 7.8%(b), 22.6%(c) grafted membranes.

Yong Wang, Zhimin Liu, Buxing Han, Zexuan Dong, Jiaqiu Wang, Donghai Sun, Ying Huang And Guanwen Chen, pH Sensitive polypropylene porous membrane prepared by grafting acrylic acid in supercritical carbon dioxide, POLYMER 45 (2004) 855860

Conclusion
It is possible to deliver a drug to a specific site, in specific time and release pattern. The constant drug level in blood or sustained drug release to avoid multiple doses . The design of a new polymer/drug pair system often requires a tedious screening to satisfy the required release pattern. Transdermal drug delivery is one of the easier mode in which polymer membranes are extensively used. Bioartificial membranes have high biocompatibility with superior mechanical properties. Temperature and PH sensitive polymer membranes intelligently response to the biological environment.

Thank You.

Some mechanisms of flow

Solution- Diffusion model

Adsorption of the species on the surface

Diffusion through the matrix

Desorption of the species

Flory-Huggins theory for solubility of solutes in polymers makes a contribution to the permeation

Flory-Huggins theory

n1 - no. of moles of solutes (drug) n2 -no. of moles of polymer 1 -Volume fraction of solute 2 -Volume fraction of the polymer 12 -Interaction parameter