Poly(Ortho esters) - American Chemical Society

Chapter 3

Poly(Ortho esters): Some Recent Developments *

Downloaded by UNIV OF GUELPH LIBRARY on July 6, 2012 | http://pubs.acs.org Publication Date: March 9, 2006 | doi: 10.1021/bk-2006-0924.ch003

Jorge Heller and John Barr A P Pharma, 123 Saginaw Drive, Redwood City, CA 94063 Corresponding author: [email protected] *

Poly(ortho esters) have been under development since the early 1970's and four distinct families have been investigated. The latest family, P O E IV, is an autocatalyzed polymer that contains a latent acid in the polymer backbone, where erosion rates can be adjusted by varying the concentration of the latent acid, and mechanical properties of the polymer can be adjusted by choice of monomers. Thus, P O E IV is a highly versatile material that is currently being commercialized for the treatment of post-operative pain and nausea.

Introduction Poly(ortho esters) have been under development since the early 1970's and during that time, four distinct families have been described (/). The four families, shown in Scheme 1, have been prepared by two general reaction processes. In one process, the polymers are prepared by a transesterification reaction, which was used for the synthesis of POE I and POE III. However, this type of reaction involves long reaction times in order to drive the equilibrium towards polymer, is very difficult to scale up, and accurate control of molecular weight is virtually impossible. For these reasons these materials have not been

© 2006 American Chemical Society

In Polymeric Drug Delivery II; Svenson, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.

29

30 commercialized, despite interesting properties, particularly for POE III, which has shown excellent ocular biocompatibility (2). +0.

O-R-

r


POE I

^ n ^ ^ o

1

XL*.POE III

POE II

(H)

— i X D ^ o - ^ C ^ — POE IV

Scheme 1. Chemical structures of the four families ofpoly(ortho esters).

A n alternate means of preparing poly(ortho esters) is by the addition of diols to diketene acetals. The rationale for selecting the diketene acetal 3,9bis(ethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane) has been described else where (3).

Results and Discussion Polymer Synthesis The synthesis shown in Scheme 2 has a number of significant advantages. Dominant among these are (i) ease of synthesis that allows easy scale-up and (ii) ability to vary polymer properties within very wide limits by choice of appropriate diol. This advantage will be elaborated further under polymer properties.

— * ^ O C X —• J J X X X ; J _ Scheme 2. General scheme for the synthesis ofpoly(ortho esters).


31


This synthesis proceeds without the evolution of volatile by-products even though it is a condensation polymerization. It is thus possible to prepare dense crosslinked materials by first preparing a ketene acetal-terminated prepolymer and then crosslinking by using diols having at least one additional functionality (hydroxy group). This principle is shown in Scheme 3. The synthesis has been scaled-up to kilogram quantities, and polymers prepared under G M P conditions are now available from a contract manufacturer.

R(OH)

3

CROSSLINKED POLYMER Scheme 3. General scheme for the synthesis of crosslinked poly(ortho esters) using alcohols with at least three functionalities.

In case of prepolymers with molecular weights low enough to exist as a viscous liquid at room temperature, drugs can be mixed into the prepolymer, followed by addition of the alcohol and crosslinking of the mixture by mild heating. Thus, sensitive materials can be incorporated without compromising their integrity. However, i f the drug has reactive hydroxy groups, it will be chemically attached to the polymer. This procedure has been used for the incorporation of ivermectin as well as the preparation of a product with iver mectin covalently attached to the polymer (4).


32 Polymer Properties


Glass Transition Temperature As already mentioned, polymer properties can be varied within very wide limits by an appropriate choice of the diol, or mixture of diols used in the synthesis. This process is illustrated in Figure 1, where the glass transition temperature of polymers prepared using a mixture of a rigid diol, transcyclohexanedimethanol, and a flexible diol, 1,6-hexane diol, was used (5). The data show a smooth change from a low of about 20°C for a polymer containing all 1,6-hexane diol to about 115°C for a polymer containing all trans-cyclohexanedimethanol. 120 UJ

D UJ CL

100-

80-

2

UJ H

Z

o 55 z

4

3500-

UJ

i g

3000-1

,

,

,

,

,

,

4

6

8

10

12

14

16

MOLE % n-DECANOL Figure 8. Effect of n-decanol on the molecular weight of a polyfortho ester) preparedfrom 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5Jundecane, 1,10decanediol and 1,10-decanediol lactide (ratio 100/70/30). (Reproduced with permissionfromReference (12). Copyright 2002 Taylor & Francis.)

Development of a Formulation to Treat Post-Operative Pain Gel-like poly(ortho esters), containing the drug mepivacaine, were used in an attempt to instill the material into a surgical incision prior to wound closure. The rationale for this treatment was to provide a high local concentration of mepivacaine within the incision, while at the same time maintaining a low systemic concentration. If the analgesic effect at the surgical site could be maintained, the patient dependence on orally administered opiates with their well-known side effects could be greatly reduced. Such materials are currently in the process of being commercialized, and a Phase II clinical trial using inguinal hernia repair is currently ongoing. The structure of the polymer is shown in Scheme 6. The composition of the clinical formulation, designated as A P F 112, is 77.6% polymer, 19.4% methoxy poly(ethylene glycol) 550 and 3% mepivacaine.


41

o +

HCMCHZCHZOJ-H

+HO-(CH .C-0)5 (CH CH 0) -H 2

R

2

2

3

1


O

0 -

X

^ O

X

O - f CH - C-0 4 - R*—O 2

O—^^O

O-R

R = R' = -(CH CH 0)32

2

Scheme 6. Structure of the poly(ortho ester) used in clinical formulation APF 112. Toxicology Studies in Preparation of an IND Filing Two types of studies were carried out, (i) using a polymer hydrolysate and (ii) using the A P F 112 formulation. Polymer Hydrolysate Hydrolyzation of the polymer into its hydrolysis products simulates the instantaneous erosion of an implant and thus represents a worse case scenario. The hydrolysate was prepared by hydrolyzing the polymer in phosphate buffered saline (PBS) at 80°C for 24 hours, adjusting the pH to 7.4 with NaOH, adding methoxy poly(ethylene glycol), mixing thoroughly, adding deionized water to adjust osmoiarity, and finally filtering through a 0.45 urn filter. The solution was then injected subcutaneously into male and female Sprague-Dowley rats and into male and female beagle dogs. In the rat study, the doses used were 0, 1, 3 and 10 mL/kg and in beagle dogs, the doses were 0, 0.05, 0.1 and 0.2 mL/kg. Both animal species were observed for 14 days and no adverse effects by clinical observation and gross necropsies were found. APF 112 Formulation The following incisional wound instillation study was carried out. A 1-cm full thickness incision was made, creating a subcutaneous pocket by blunt dissection. The A P F 112 formulation was administered into the subcutaneous pocket and the skin closed with 4-0 nylon sutures, which were removed after 7 days. The study was carried out using Sprague-Dowley male and female rats,


42 using a 500 and 1000 single dose. The rats were sacrificed at day 8. Both doses were well tolerated, but the 1000 |LIL dose resulted in leakage and wound distension.


Conclusions Synthesis and characterization of various poly(ortho esters) has been described. The physical behavior of this material can easily be changed by its composition and the choice of its constituent components. The suitability of poly(ortho esters) in medical applications was demonstrated in several examples. One poly(ortho ester) formulation, designated as A P F 112, is currently in clinical trials.

References 1.

2.

3. 4.

5.

6.

7.

8. 9.

Heller, J.; Barr, J.; Ng, S. Y.; Schwach-Abdellaoui, K.; Gurny, R. Poly (ortho esters): Synthesis, characterization, properties and uses. Adv. Drug. Deliv. Rev. 2002, 54, 1015-1039. Einmahl, S.; Behar-Cohen, F.; Tabatabay, C.; Savoldelli, M.; D'Hermies, F.; Chauvaud, D.; Heller, J.; Gurny, R. A viscous bioerodible poly(ortho ester) as a new biomaterial for intraocular application. J. Biomed. Mater. Sci. 2000, 50, 566-573. Heller, J.; Barr, J. Poly(ortho esters) - From concept to reality. Biomacromol. 2004, 5, 1625-1632. Shih, C.; Seward, R. L.; In vivo and in vitro release of ivermectin from poly (ortho ester) matrices. I. Crosslinked matrix prepared from ketene acetal end-capped prepolymer. J. Control. Rel. 1993, 25, 155-162. Heller, J.; Penhale, D. W. H.; Fritzinger, B . K.; Rose, J. E.; Helwing, R. F. Controlled release of contraceptive steroids from biodegradable poly(ortho esters). Contracept. Deliv. Syst. 1983, 4, 43-53. Trends and Future Perspectives in Peptide and Protein Drug Delivery; Lee, V . H . L.; Hashida, M.; Mizushima, Y . , Eds.; Harwood Academic Publishers: Switzerland, 1995; pp. 39-56. Schwach-Abdellaoui, K.; Heller, J.; Gurny, R. Hydrolysis and erosion studies of autocatalyzed poly(ortho esters) containing lactoyl-lactyl acid dimers. Macromol. 1999, 32, 301-307. Scaffolding in Tissue Engineering; M a , P. X.; Elisseeff, J., Eds.; Marcel Dekker, New York, in press. Heller, J.; Barr, J.; Ng, S. Y . ; Shen, H-R.; Schwach-Abdellaoui, K . ; Einmahl, S.; Rothen-Weinhold, A.; Gurny, R. Poly(ortho esters) - Their



43 development and some recent applications. Eur. J. Pharm. Biopharm. 2000, 50, 1221-128. 10. Ng, S. Y.; Shen, H-R.; Lopez, E.; Zherebin, Y . ; Barr, J.; Schacht, E.; Heller, J. Development of a poly(ortho ester) prototype with a latent acid in the polymer backbone for 5-fluorouracil delivery. J. Control. Rel. 2000, 65, 367-374. 11. Wang, C.; Ge, Q.; Ting, D.; Shen, H-R.; Chen, J.; Eisen, H . N.; Heller, J.; Langer, R.; Putnam, D. Molecularly engineered poly(ortho esters) micro spheres for enhanced delivery of D N A vaccines, Nature Mater. 2004, 3, 190-196. 12. Schwach-Abdellaoui, K.; Heller, J.; Gurny, R. Control of molecular weight for autocatalyzed poly(ortho esters) obtained by polycondensation reaction, Int. J. Pol. Anal. and Charact. 2002, 7, 145-161.


Poly(Ortho esters) - American Chemical Society

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