Nonproprietary Names
None adopted.
Synonyms
See Table I.
Chemical Name and CAS Registry Number
See Table I.
Empirical Formula and Molecular Weight
Aliphatic polyesters are synthetic homopolymers or copolymers of lactic acid, glycolic acid, lactide, glycolide and e-hydroxycaproic acid. Typically, the molecular weights of homopolymers and copolymers range from 2000 to >100000Da.
Structural Formula
Functional Category
Bioabsorbable material; biocompatible material; biodegradable material.
Applications in Pharmaceutical Formulation or Technology
Technology Owing to their reputation as safe materials and their biodegradability, aliphatic polyesters are primarily used as biocompatible and biodegradable carriers in many types of implantable or injectable drug-delivery systems for both human and veterinary use. Examples of implantable drug delivery systems include rods,(1) cylinders, tubing, films,(2) fibers, pellets, and beads.(3) Examples of injectable drug-delivery systems include microcapsules,(4) microspheres,(5) nanoparticles, and liquid injectable controlled-release systems such as gel formulations.(6)
Description
Aliphatic polyesters are a group of synthesized homopolymers or copolymers. They are nontoxic and can easily be fabricated into a variety of novel devices, such as rods, screws, nails, and cylinders. The polymers are commercially available in varying molecular weights as both homopolymers and copolymers. Molecular weights of polyesters range from 2000Da to greater than 100000Da. Co-monomer ratios of lactic acid and glycolic acid (or lactide and glycolide) for poly(DL-lactide-co-glycolide) range from 85:15 to 50:50. Table I shows the chemical and trade names of different commercially available aliphatic polyesters.
Pharmacopeial Specifications
—
Typical Properties
For typical physical and mechanical properties of the aliphatic polyesters, see Tables II, III, IV, V, VI, and VII. Polymer composition and crystallinity play important roles in the solubility of these aliphatic polyesters. The crystalline homopolymers of glycolide or glycolic acid are soluble only in strong solvents, such as hexafluoroisopropanol. The crystalline homopolymers of lactide or lactic acid also do not have good solubility in most organic solvents. However, amorphous polymers of DL-lactide or DL-lactic acid and copolymers of lactide or lactic acid with a low glycolide or glycolic acid content are soluble in many organic solvents (Table II). Aliphatic polyesters are slightly soluble or insoluble in water, methanol, ethylene glycol, heptane, and hexane.
Stability and Storage Conditions
The aliphatic polyesters are easily susceptible to hydrolysis in the presence of moisture. Hence, they should be packaged under highpurity dry nitrogen and properly stored in airtight containers, preferably refrigerated at below 08C. It is necessary to allow the polymers to reach room temperature in a dry environment before opening the container. After the original package has been opened, it is recommended to re-purge the package with high-purity dry nitrogen prior to resealing.
Incompatibilities
—
Method of Manufacture
Generally, aliphatic polyesters can be synthesized via polycondensation of hydroxycarboxylic acids and catalytic ring-opening polymerization of lactones. Ring-opening polymerization is preferred because polyesters with high molecular weights can be 23 Generic name Composition (%) Synonyms Trade name Manufacturer CAS name CAS number Glycolide Poly(L-lactide) 0 0 L-PLA Lactel L-PLA Durect Poly[oxy[(1S)-1-methyl-2-oxo-1,2- [26161-42-2] 100 L Lakeshore ethanediyl]] Resomer L 206 S, 207 S, 209 S, BI 210, 210 S Poly(DL-lactide) 100 0 0 DL-PLA Lactel DL-PLA Durect 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [26680-10-4] Purasorb PDL 02A, 02, 04, 05 Purac homopolymer Resomer R 202 S, 202 H, 203 BI S, 203 H 100 DL 7E Lakeshore 85 15 0 Resomer LG 855 S, 857 S BI 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [30846-39-0] glycolide) (3S,6S)-, polymer with 1,4-dioxane-2,5- dione Poly(L-lactide-co- 82 18 0 Resomer LG 824 S BI 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [30846-39-0] glycolide) (3S,6S)-, polymer with 1,4-dioxane-2,5- dione 10 90 0 Resomer GL 903 BI 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [30846-39-0] glycolide) (3S,6S)-, polymer with 1,4-dioxane-2,5- dione Poly(DL-lactide-co- 85 15 0 Polyglactin;DL- Lactel 85 : 15 DL-PLG Durect 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [26780-50-7] glycolide) PLGA (85 : 15) 8515 DLG 7E Lakeshore polymer with 1,4-dioxane-2,5-dione Resomer RG 858 S BI Poly(DL-lactide-co- 75 25 0 Polyglactin;DL- Lactel 75:25 DL-PLG Durect 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [26780-50-7] glycolide) PLGA (75 : 25) Purasorb PDLG 7502A, 7502, Purac polymer with 1,4-dioxane-2,5-dione 7507 Resomer RG 752 H, 752 S, 753 BI S, 755 S, 756 S 7525 DLG 7E Lakeshore Poly(DL-lactide-co- 65 35 0 Polyglactin;DL- Lactel 65:35 DL-PLG Durect 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [26780-50-7] glycolide) PLGA (65 : 35) 6535 DLG 7E Lakeshore polymer with 1,4-dioxane-2,5-dione Resomer RG 653 H BI Poly(DL-lactide-co- 50 50 0 Polyglactin;DL- Lactel 50:50 DL-PLG Durect 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [26780-50-7] glycolide) PLGA (50 : 50) 5050 DLG 7E, 5E, 1A, 2A, 3A, Lakeshore polymer with 1,4-dioxane-2,5-dione 4A, 4.5A Purasorb PDLG 5002A, 5002, Purac 5004A, 5004, 5010 Resomer RG 502, 502H, 503, BI 503H, 504, 504H, 509S Poly-e-caprolactone 0 0 100 PCL Lactel PCL Durect 2-Oxepanone, homopolymer [24980-41-4] 100 PCL Lakeshore Poly(DL-lactide-co-e- 85 0 15 8515 DL/PCL Lakeshore 1,4-Dioxane-2,5-dione,3,6-dimethyl-, [70524-20-8] caprolactone) polymer with 2-oxepanone 80 0 20 DL-PLCL (80 : 20) Lactel 80 : 20 DL-PLCL Durect 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [70524-20-8] caprolactone) polymer with 2-oxepanone 25 0 75 DL-PLCL (25 : 75) Lactel 25 : 75 DL-PLCL Durect 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [70524-20-8] caprolactone) polymer with 2-oxepanone 70 0 30 Resomer LC 703 S BI 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [65408-67-5] caprolactone) (3S,6S)-, polymer with 2-oxepanone Poly(L-lactide-co-e- 85 0 15 8515 L/PCL Lakeshore 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [65408-67-5] caprolactone) (3S,6S)-, polymer with 2-oxepanone Poly(L-lactide-co-e- 75 0 25 7525 L/PCL Lakeshore 1,4-Dioxane-2,5-dione, 3,6-dimethyl-, [65408-67-5] caprolactone) (3S,6S)-, polymer with 2-oxepanone Table II: Typical physical and mechanical properties of the aliphatic polyesters.(a) 50/50 DL-PLG 65/35 DL-PLG 75/25 DL-PLG 85/15 DL-PLG DL-PLA L-PLA PGA PCL Molecular weight 40 000–100 000 40 000–100 000 40 000–100 000 40 000–100 000 40 000–100 000 >100 000 >100 000 80 000–150 000 Inherent viscosity (dL/g) 0.5–0.8(b) 0.5–0.8(b) 0.5–0.8(c) 0.5–0.8(c) 0.5–0.8(c) 0.9–1.2(c) 1.4–1.8(b) 1.0–1.3(c) Melting point (8C) Amorphous Amorphous Amorphous Amorphous Amorphous 173–178 225–230 58–63 Glass transition temperature (8C) 45–50 45–50 50–55 50–55 50–60 60–65 35–40 –65 to –60 Color White to light gold White to light gold White to light gold White to light gold White White Light tan White Solubility (at 5% w/w)(d) MeCl2, THF, EtOAc, C3H6O, CHCl3, HFIP MeCl2, THF, EtOAc, C3H6O, CHCl3, HFIP MeCl2, THF, EtOAc, C3H6O, CHCl3, HFIP MeCl2, THF, EtOAc, C3H6O, CHCl3, HFIP MeCl2, THF, EtOAc, C3H6O, CHCl3, HFIP MeCl2, CHCl3, HFIP HFIP MeCl2, CHCl3, HFIP Approx. resorption (months) 1–2 3–4 4–5 5–6 12–16 >24 6–12 >24 Specific gravity 1.34 1.30 1.30 1.27 1.25 1.24 1.53 1.11 Tensile strength (psi) Elongation (%) 6000–8000 3–10 6000–8000 3–10 6000–8000 3–10 6000–8000 3–10 4000–6000 3–10 8000–12 000 5–10 10 000þ 15–20 3000–5000 300–500 Modulus (psi) 2–4 105 2–4 105 2–4 105 2–4 105 2–4 105 4–6 105 1 106 3–5 104 Note: DL-PLG: DL-poly(lactide-co-glycolide); DL-PLA: DL-polylactide; L-PLA: L-polylactide; PGA: polyglycolide; PCL: poly-e-caprolactone. (a) Specifications obtained from Durect. (b) (HFIP) hexafluoroisopropanol. (c) (CHCl3) chloroform. (d) Partial listing only: MeCl2, methylene chloride; THF, tetrahydrofuran; EtOAc, ethyl acetate; HFIP, hexafluoroisopropanol; C3H6O, acetone. Aliphatic Polyesters Table III: General mechanical properties of selected aliphatic polyesters.(a) Property Polymer 5050 DL 100 DL 100 L (Custom) 90/10 L/DL (Custom) Composition Poly (DL-lactide-co-glycolide) (50 : 50) Poly (DL-lactide) Poly (L-lactide) Poly (L-lactide-co-DL-lactide) Break stress (psi) 8296 6108 7323 7614 Strain at break (%) 5.2 5.0 5.5 5.2 Yield stress (psi) 8371 6666 7678 8414 Strain at yield (%) 5.1 3.7 4.9 4.5 Modulus (psi) 189 340 207 617 182 762 210 680 (a) Specification obtained fro m Lakeshore Biomaterials. Table IV: Mechanical properties of poly(L-lactide/caprolactone).(a) Property Poly (L-lactide/caprolactone) grade 50/50 75/25 85/15 90/10 95/05 Tensile strength (psi) At maximum 80 1488 3254 6232 6900 At 100% 79 400 1822 — — At 300% 44 950 2615 — — Elongation (%) To yield >1000 >400 >6.4 8.1 1.6 To failure >1000 >400 >500 8.1 1.6 Modulus (kpsi) 0.1 5.3 84 167 185 Shore D-hardness 5 52 87 91 95 Specific gravity 1.2 1.2 1.23 1.25 1.26 Compression molding temperature (8C) 73–130 130 15 140 10 165 5 165 5 (a) Specifications obtained from Lakeshore Biomaterials. Table VI: Glass transition temperature and melting point of selected biodegradable polymers.(a) Polymer Composition Glass transition temperature (8C) Melting point (8C) 100 PGA Poly (glycolic acid) 35–40 225–230 100 L Poly (L-lactide) 56–60 173–178 9010 G/L Poly (L-lactide-co-glycolide)(10 : 90) 35–45 180–200 100 DL Poly (DL-lactide) 50–55 Amorphous(b) 8515 DL/G Poly (DL-lactide-co-glycolide) (85 : 15) 50–55 Amorphous(b) 7525 DL/G Poly (DL-lactide-co-glycolide) (75 : 25) 48–53 Amorphous(b) 6335 DL/G Poly (DL-lactide-co-glycolide) (65 : 35) 45–50 Amorphous(b) 5050 DL/G Poly (DL-lactide-co-glycolide) (50 : 50) 43–48 Amorphous(b) 8515 DL/PCL Poly (DL-lactide-co-caprolactone) (85 : 15) 20–25 Amorphous(b) 8515 L/PCL Poly (L-lactide-co-caprolactone) (85 : 15) 20–25 Amorphous(b) 7525 L/PCL Poly (L-lactide-co-caprolactone) (75 : 25) 13–20 Amorphous(b) 100 PCL Poly (caprolactone) (60) – (65) 60 (a) Specifications obtained from Lakeshore Biomaterials. (b) Process temperature range: 140–1608C. Table VII: Solubility of selected aliphatic polyesters.(a) Polymer Polymer Solvent Ethyl acetate Methylene chloride Chloroform Acetone Dimethyl formamide (DMF) Tetrahydrofuran (THF) Hexafluoroisopropanol (HFIP) Poly (L-lactide) NS S S NS NS NS S Poly (DL-lactide) S S S S S S S Poly (DL-lactide-co-glycolide) (85 : 15) S S S S S S S Poly (DL-lactide-co-glycolide) (75 : 25) S S S S S S S Poly (DL-lactide-co-glycolide) (65 : 35) S S S S S S S Poly (DL-lactide-co-glycolide) (50 : 50) SS S S SS S SS S Poly (caprolactone) S S S S S S S Poly (L-lactide-co-caprolactone) (75 : 25) S S S S S S S Poly (DL-lactide-co-caprolactone) (80 : 20) S S S S S S S Poly (glycolic acid) NS NS NS NS NS NS S (a) Specifications obtained from Lakeshore Biomaterials. NS, not soluble; SS, slightly soluble (degree of solubility is dependent on molecular weight or inherent viscosity); S, soluble. Table V: Mechanical properties of poly (DL-lactide/caprolactone).(a) Property Poly(DL-lactide/caprolactone) grade 60/40 75/25 85/15 90/10 95/05 Tensile strength (psi) At maximum 65 1300 1555 4453 5493 At 100% 65 224 1555 — — At 300% 43 332 1041 — — Elongation (%) To yield — — — 5.6 — To failure >400 >600 >500 5.6 7.2 Modulus (kpsi) 0.1 1.05 6.04 106 135 Shore D-hardness 0 42 79 88 95 Specific gravity — 1.20 1.22 1.24 — Compression molding temperature (8C) — 82–140 82–140 82–140 120 (a) Specifications obtained from Lakeshore Biomaterials. produced. Moreover, the dehydration of hydroxycarboxylic acids to form lactones does not have to be carried to a high degree of completion. Lactones can easily be purified owing to the differences of their physical and chemical properties from those of the corresponding hydroxycarboxylic acid. The esterification of the carboxylic acid end group makes polymers more hydrophobic, which decreases the hydrolytic degradation rate of the polymers in the presence of water or moisture.
Safety
Poly(lactic acide) or poly(lactide), poly(glycolic acid) or poly(glycolide), poly (lactic-co-glycolic acid) or poly(lactide-co-glycolide), and polycaprolactone are used in parenteral pharmaceutical formulations and are regarded as biodegradable, biocompatible, and bioabsorbable materials. Their biodegradation products are nontoxic, noncarcinogenic, and nonteratogenic. In general, these polyesters exhibit very little hazard.
Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity of material handled. Contact with eyes, skin, and clothing, and breathing the dust of the polymers should be avoided. Aliphatic polyestersproduceacidmaterialssuchashydroxyaceticand/orlactic acidinthepresenceofmoisture;thus,contactwithmaterialsthatwill react with acids, especially in moist conditions, should be avoided.
Regulatory Status
GRAS listed. Included in the Canadian List of Acceptable Nonmedicinal Ingredients. Poly(lactide) and poly(lactide-co-glycolide) have been used in medical products and medical devices approved by the FDA. 17 Related Substances Lactic acid.
Comments
Aliphatic polyesters are a group of synthesized, nontoxic, biodegradable polymers. In an aqueous environment, the polymer backbone undergoes hydrolytic degradation, through cleavage of the ester linkages, into nontoxic hydroxycarboxylic acids. Aliphatic polyesters are eventually metabolized to carbon dioxide and water, via the citric acid cycle. The rate of biodegradation and drug-release characteristics from injectable drug-delivery systems formulated with the aliphatic polyesters can be controlled by changing the physicochemical properties of the polymers, such as crystallinity, hydrophobicity, monomer stereochemistry, copolymer ratio, end group, and Aliphatic Polyesters polymer molecular weight or by changing the porosity and geometry of the formulation. Due to their ability to form complexes with heavy metal ions, aliphatic polyesters are added to skin-protective ointments.(7) 19 Specific References 1 Shim IK et al. Healing of articular cartilage defects treated with a novel drug-releasing rod-type implant after microfracture surgery. J Control Release 2008; 129: 187–191. 2 Aviv M et al. Gentamicin-loaded bioresorbable films for prevention of bacterial infections associated with orthopedic implants. J Biomed Mater Res A 2007; 83: 10–19. 3 Wang G et al. The release of cefazolin and gentamicin from biodegradable PLA/PGA beads. Int J Pharm 2004; 273: 203–212. 4 Snider C et al. Microenvironment-controlled encapsulation (MiCE) process:effectsofPLGAconcentration,flowrate,andcollectionmethod on microcapsule size and morphology. Pharm Res 2008; 25: 5–15. 5 Giovagnoli S et al. Physicochemical characterization and release mechanism of a novel prednisone biodegradable microsphere formulation. J Pharm Sci 2008; 97: 303–317. 6 Zare M et al. Effect of additives on release profile of leuprolide acetate in an in situ forming controlled-release system: in vitro study. J Appl Polym Sci 2008; 107: 3781–3787. 7 Hoeffner EM et al, ed. Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th edn. Munich, Germany: Editio Cantor Verlag Aulendorf, 2002; 1270.
General References
Alexis F. Factors affecting the degradation and drug-release mechanism of poly(lactic acid) and poly[(lactic acid)-co-(glycolic acid)]. Polymer Int 2005; 54: 36–46. Allison SD. Effect of structural relaxation on the preparation and drug release behavior of poly(lactic-co-glycolic)acid microparticle drug delivery systems. J Pharm Sci 2008; 97: 2022–2035. Boehringer Ingelheim. Resomer. http://www.boehringer-ingelheim.com/corporate/ic/pharmachem/products/resomer.asp (accessed 16 February 2009). Durect Corporation. Lactel absorbable polymers. http://www.durect.com/ wt/durect/page_name/bp (accessed 16 February 2009). Giteau A et al. How to achieve sustained and complete protein release from PLGA-based microparticles? Int J Pharm 2008; 350: 14–26. Johansen P et al. Development of synthetic biodegradable microparticulate vaccines: a roller coaster story. Expert Rev Vaccines 2007; 6: 471–474. Jostel A, Shalet SM. Prospects for the development of long-acting formulations of human somatropin. Treat Endocrinol 2006; 5: 139–145. Kulkarni RK et al. Biodegradable poly(lactic acid) polymers. J Biomed Mater Res 1971; 5: 169–181. Lakeshore Biomaterials. http://www.lakeshorebio.com/products.html (accessed 16 February 2009). Lewis H. Controlled release of bioactive agents from lactide/glycolide polymers. Chasin M, Langer R, eds. Biodegradable Polymers as Drug Delivery Systems. New York: Marcel Dekker, 1990; 1–41. Li SM et al. Structure–property relationships in the case of the degradation of massive aliphatic poly-(a-hydroxy acids) in aqueous media, part 1: poly(dl-lactic acid). J Mater Sci Mater Med 1990; 1: 123–130. Mohamed F, van der Walle CF. Engineering biodegradable polyester particles with specific drug targeting and drug release properties. J Pharm Sci 2008; 97: 71–87. Nguyen TH et al. Erosion characteristics of catalyzed poly(orthoester) matrices. J Control Release 1987; 5: 1–12. Olivier JC. Drug transport to brain with targeted nanoparticles. NeuroRx 2005; 2: 108–119. Pitt CG et al. Sustained drug delivery systems II: factors affecting release rates from poly (e-caprolactone) and related biodegradable polyesters. J Pharm Sci 1979; 68: 1534–1538. Purac America. http://www.purac.com (accessed 16 February 2009). Reed AM, Gilding DK. Biodegradable polymers for use in surgerypoly(glycolic)/poly(lactic acid) homo and copolymers: 2. In vitro degradation. Polymer 1981; 22: 494–498. Shah SS et al. Poly(glycolic acid-co-DL lactic acid): diffusion or degradation controlled drug delivery? J Control Release 1992; 18: 261–270. Smith AW. Biofilms and antibiotic therapy: is there a role for combating bacterial resistance by the use of novel drug delivery systems? Adv Drug Deliv Rev 2005; 57: 1539–1550. Alitame Tamilvanan S et al. Manufacturing techniques and excipients used during the design of biodegradable polymer-based microspheres containing therapeutic peptide/protein for parenteral controlled drug delivery. PDA J Pharm Sci Technol 2008; 62: 125–154. Vert M et al. New insights on the degradation of bioresorbable polymeric devices based on lactic and glycolic acids. Clin Mater 1992; 10: 3–8. Visscher GE et al. Biodegradation and tissue reaction to 50:50 poly(DLlactide-co-glycolide) microcapsules. J Biomed Mater Res 1985; 19: 349– 365. Williams DF. Mechanisms of biodegradation of implantable polymers. Clin Mater 1992; 10: 9–12.
Author
s RK Chang, W Qu, AJ Shukla, N Trivedi.
Date of Revision
16 February 2009.