Degradable Polymeric Carriers for Parenteral Controlled Drug Delivery

2

Contents

• Abstract • Introduction • Factors influencing drug release from

degradable polymer matrices• Principles of polymer degradation and erosion• Drug release characteristics of degradable

polymeric carriers• Strategies to control drug release rates from

degradable polymers toward zero order profiles • Conclusion

3

4

Introduction • Microencapsulation concepts developed in the 1980s

and 1990s of the last century led to injectable particulate depot formulations, e.g., for leuprolide acetate (Lupron® Depot, Enantone®, Trenantone®) and goserelin acetate (Zoladex®)

• These matrices typically consist of degradable polymers, which slowly degrade under physiological conditions and thus avoid accumulation of exhausted drug carriers in the body or the need of a second surgery for ex-plantation.

• Degradability is often a strong benefit in terms of patients’ convenience, marketing, and hospitalization costs.

5

• The term degradation (or biodegradation if driven by contributions of living cells) usually refers to a breakdown of polymers at the molecular level, i.e., chain cleavage that leads to degradation products that are safely eliminated by the body.

Cont’d

6

• In contrast, the term erosion refers to the process of polymer mass loss, which includes not only degradation but several other processes, such as water uptake leading to microscopic or macroscopic changes of the structural integrity of the drug carrier and eventual removal of degraded or nondegraded material to the surrounding medium

Cont’d

7

• In principle, drug release from hydrophobic polymers can be controlled by diffusion and/or degradation of the matrix, typically by spontaneous hydrolysis.

• The uptake of distinct quantities of water into the matrix is required to enable drug diffusion and hydrolytic cleavage of polymer chains.

Cont’d

8

• If the extent of water uptake is rather low, in this case, the type of erosion mechanism may largely depend on the involved rates of two mechanisms, water uptake and hydrolytic degradation, and which of them is dominating over the other.

• In this chapter, temporal controlled injectable and implantable delivery systems are reviewed, which involve degradation and erosion of the polymer matrix.

Cont’d

9

Factors Influencing Drug Release from Degradable Polymer Matrices

• Factors controlling drug release behavior can be classified into two major groups, i.e.,

• (1) physical processes and chemical/physicochemical molecular properties associated with the involved materials and

• (2) the environmental conditions as well as properties related to the engineered shape of the drug carrier.

10

Fig. 8.1 Scheme of major factors that may influence drug release rates from drug carriers based on degradable polymers

11

• Other important parameters or processes that contribute to the release profile are

• Indication and Required Release Rates Define Preferred Carrier Type

• Effect of Environmental Conditions on Release• Impact of Drug Properties• Contributions of Osmotically Mediated Mechanisms

Cont’d

12

Indication and Required Release Rates Define Preferred Carrier Type

• The desired release rates, duration of release and total dose,

• The route of administration (e.g., sc, im, ip, or site of surgical placement),

• Type of drug carrier (e.g., particles or implants), • Specific shapes or dimensions of the carrier (e.g.,

particle size distribution or shape of implants such as polymeric stents).

• Depending on these application-dictated requirements, a specific drug carrier may be selected that fits the indication of interest

13

Effect of Environmental Conditions on Release

• The drug release rates from a specific carrier are largely affected by,

• environmental or physiological conditions,• drug physicochemical properties,• matrix ultrastructure and shape, • osmotically driven mechanisms,• biodegradation and erosion pathways of the

polymeric matrix.

14

Impact of Drug Properties

• Low solubility drugs are typically characterized by lower diffusion rates due to a lower concentration gradient of the drug from the inside to the outside the matrix.

• Large substances such as proteins do often not show release by diffusion through a dense, nonporous polymer matrix.

• Noncovalent binding between drug and polymer may reduce release rates or cause incomplete release until complete erosion of the polymer.

• Molecular weights and hydrodynamic radii.

15

Contributions of Osmotically Mediated Mechanisms

• In the polymer matrix, osmotic pressure builds up by encapsulated highly water-soluble compounds, resulting in water influx.

• Such water penetration through the polymer phase and/or pore network can result in rupture of pore walls for rapid release out of the polymer and/or release by osmotic convective mass transfer.

16

• Moreover, polymer properties have a very important impact on drug release rates from degradable matrices. This includes several aspects, e.g.

• polymer hydrophilicity/hydrophobicity, • drug–polymer interactions, • polymer mesh width,• drug diffusibility, polymer morphology and physical

state,• polymer degradation and erosion behavior.

Cont’d

17

Principles of Polymer Degradation and Erosion

• Principles of Polymer Degradation:• The degradation i.e. the molecular breakdown of

polymers is governed by• chemical composition, • architecture and morphology, • environmental conditions and device properties. • e.g. , in hydrolytically degrading (co)polymers, the

uptake of water into the matrix is an essential precondition for chain cleavage and is affected by the matrix hydrophilicity as a function

18

• Three concepts of polymer degradation with relevance for controlled drug release can be differentiated

• First, linear polymers as most often used for controlled drug release matrices can degrade into mono- or oligomers by random or selective scission of bonds in the polymer main chain.

• All commercialized drug loaded implants and microparticle products based on polyesters or polyanhydrides follow this pathway.

Cont’d

19

• Second, linear polymers may contain side chains that, after cleavage, convert into hydrophilic or charged groups attached to the polymer backbone, which enable aqueous solubility of the polymer. Besides other pathways.

• This mechanism is discussed as the major pathway in polyalkyl-cyanoacrylate degradation.

• Third, polymer networks may disintegrate into water-soluble linear polymer chains by selective degradation of netpoints.

• Polyacrylate-based networks crosslinked with hydrolytically cleavable copolyester segments are examples for hydrophobic matrices.

Cont’d

20

• Principles of Erosion Triggering Mass Loss:

• Polymer erosion, i.e., the release of degraded or nondegraded polymeric material, resulting in mass loss of the sample.

• Degradation induced by exposure to different factors including, e.g., heat, light, or oxidative stress.

• copolymers synthesized from dilactides and diglycolide (PLGA) is the example of controlled release matrices.

21

• For polymer erosion that relies on aqueous hydrolysis, four different steps can be differentiated, i.e.,

• (1) wetting of the polymer surface including a possible internal porous structure,

• (2) water uptake with a material-specific rate into the polymer bulk,

• (3) degradation of the polymer following a characteristic pathway with a material- and possibly geometry dependent rate, and

• (4) if possible, diffusion controlled removal of degradation products.

Cont’d

22

• For instance, incorporation of acidic substances into the matrix acting as catalysts can increase the degradation rate, thus changing degradation pattern and drug release to a surface erosion controlled mechanism for certain polymers.

• However, occasionally observed higher degradation rates in vivo are repeatedly assigned to enzymatic catalysis, but may also be based on other factors, e.g. inflammatory cell/tissue responses or plasticization of the polymer by molecules present in vivo.

Cont’d

23

Drug Effects on Polymer Degradation

• The incorporation of any substances including drugs into a polymer matrix may change the polymers degradation behavior.

• This is very obvious in the case of embedded highly soluble drugs or additives of similar properties, which may change the osmotic pressure in the matrix and increase water uptake.

• E.g., an increased catalytic degradation of PLGA implants was observed depending on the loading with a water-soluble N-acetyl cysteine, which enhanced water uptake.

24

• For basic drugs, e.g., thioridazine, an amine catalyzed hydrolysis of the polymer matrix during the particle preparation and a faster release were observed,

• This could be reduced by performing the o/w emulsification at lower temperatures or erasing the drug’s basicity by the formation of salts.

Cont’d

25

 Drug Release Characteristics of Degradable

Polymeric Carriers

• Polymers in Commercial Parenteral Drug Delivery Products:

• The employed carrier strategies include microparticles, preformed implants, and in situ forming implants.

• Importantly, in all but one of the so far commercialized products, PLA/PLGA is used as matrix polymer.

26

27

Microparticles

• The largest number of degradable parenteral controlled release products are based on microparticles as drug carriers.

• Beneficial aspects of microparticles as drug depots compared to preformed implants include their injectability through needles of smaller diameters as well as the advantages of all multiple unit dosage forms, i.e., a possibly better average reproducibility of their properties.

28

Microencapsulation Techniques

29

Challenges associated with encapsulation

30

Cont’d

31

32

Preformed Implants

• Preformed implants in the classical rod-like shape with the single functionality to act as drug depot, processing of drug loaded degradable polymers into advanced shapes has opened new fields of application that combine drug release and a supporting function.

• Particularly the stent technology for the treatment of coronary artery diseases is demanding such degradable material concepts

33

Preparation Techniques

34

Challenges associated with preformed implants

35

Cont’d

36

Cont’d

37

In Situ Forming Drug Depots

• In situ implants are formed in the tissue after injection, mostly due to polymer precipitation from organic solutions.

• In situ forming gels, i.e., solvent rich matrices consisting of hydrophilic or amphiphilic molecules, may employ various mechanisms of intermolecular binding,

• (1) thermosensitive materials gelling upon decrease in temperature include materials like block copolymers

38

• (2) thermosensitive materials, which gel upon increase in temperature, gelation occurs, e.g. due to the formation of block copolymer micelles

• (3) covalent crosslinking of network precursors, e.g. by enzymatic reactions

• (4) ionic crosslinking, e.g. of charged polymers• (5) pH changes, e.g. for charged polymers such

as chitosan

Cont’d

39

Cont’d

40

Strategies to Control Drug Release Rates from Degradable Polymers Toward Zero

Order Profiles• Relevance of In Vitro Zero Order Release and

Common Limitations:• Research on controlled release formulations aims to

provide delivery systems that show zero order drug release i.e., constant release rates over time.

•  for degradable matrix polymers, e.g. plasticization, potential catalytic activities of enzymes, or possible alterations in local environment due to cellular immune response, may have to be included for in vitro zero order release.

41

• Approaches to overcome undesired high initial release include,

• improve miscibility of the drug and the polymer, • to reduce diffusion to interfaces by advanced

carrier processing techniques.• In addition to the drug/polymer properties on the

molecular level, processing-derived properties of the carrier such as the surface area and the porosity will impact the release kinetics.

Cont’d

42

Conclusion

• Degradable, polymer-based drug carriers remain a scientifically and commercially important strategy to control the release of bioactive molecules over time periods ranging from several days to several months.

• Drug release from these carriers is governed by a complex interplay of parameters including drug properties, polymer degradation/erosion characteristics, and osmotically driven mechanisms, as well as environmental conditions and processing-derived device properties

43