Comments

Alginic acid dispersions are best prepared by pouring the alginic acid slowly and steadily into vigorously stirred water. Disper- sions should be stirred for approximately 30 minutes. Premix- ing the alginic acid with another powder, such as sugar, or a water-miscible liquid such as ethanol (95%) or glycerin, aids dispersion.

When using alginic acid in tablet formulations, the alginic acid is best incorporated or blended using a dry granulation process.

A specification for alginic acid is contained in the Food Chemicals Codex (FCC).

The EINECS number for alginic acid is 232-680-1.

Specific References

Shotton E, Leonard GS. Effect of intragranular and extragranular disintegrating agents on particle size of disintegrated tablets. J Pharm Sci 1976; 65: 1170–1174.

Esezobo S. Disintegrants: effects of interacting variables on the tensile strengths and disintegration times of sulfaguanidine tablets. Int J Pharm 1989; 56: 207–211.

Tissie G, Sebastian C, Elena PP, Driot JY, Trinquand C. Alginic acid effect on carteolol ocular pharmacokinetics in the pigmented rabbit. J Ocul Pharmacol Ther 2002; 18(1): 65–73.

Vatier J, Vallot T, Farinotti R. Antacid drugs: multiple but too often unknown pharmacological properties. J Pharm Clin 1996; 15(1): 41–51.



Stanciu C, Bennett JR. Alginate/antacid in the reduction of gastro- oesophageal reflux. Lancet 1974; i: 109–111.

Boisson-Vidal C, Haroun F, Ellouali M, et al. Biological activities of polysaccharides from marine algae. Drugs Future 1995; 20(Dec): 1247–1249.

Joseph I, Venkataram S. Indomethacin sustained release from alginate-gelatin or pectin-gelatin coacervates. Int J Pharm 1995; 125: 161–168.

Machluf M, Regev O, Peled Y, et al. Characterization of microencapsulated liposome systems for the controlled delivery of liposome-associated macromolecules. J Control Release 1997; 43: 35–45.

Murata Y, Sasaki N, Miyamoto E, Kawashima S. Use of floating alginate gel beads for stomach-specific drug delivery. Eur J Pharm Biopharm 2000; 50(2): 221–226.

Larma I, Harjula M. Stable compositions comprising levosimen- dan and alginic acid. Patent No: WO9955337; 1999.

Remunan-Lopez C, Bodmeier R. Mechanical, water uptake and permeability properties of crosslinked chitosan glutamate and alginate films. J Control Release 1997; 44: 215–225.

Cohen S, Lobel E, Treygoda A, Peled Y. Novel in situ-forming opthalmic drug delivery system from alginates undergoing gelation in the eye. J Control Release 1997; 44: 201–208.

Gradl T. Use of alginic acid and/or its derivatives and salts for combating or preventing diseases. Patent No: DE19723155; 1998.

Tadashi Y, Aki H, Hanae W, Koji T, Makoto H. Alginic acid oligosaccharide suppresses Th2 development and IgE production by inducing IL-12 production. Int Arch Allergy Imm 2004; 133(3):

239–247.

Vandenbossche GMR, Remon J-P. Influence of the sterilization process on alginate dispersions. J Pharm Pharmacol 1993; 45: 484–486.

Henderson AK, Ranger AF, Lloyd J, et al. Pulmonary hypersensi- tivity in the alginate industry. Scott Med J 1984; 29(2): 90–95.

FAO/WHO. Evaluation of certain food additives and naturally occurring toxicants. Thirty-ninth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1993; No. 837.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 101–102.

General References

Marshall PV, Pope DG, Carstensen JT. Methods for the assessment of the stability of tablet disintegrants. J Pharm Sci 1991; 80: 899–903.

Authors

JW McGinity, MA Repka.

Date of Revision

23 August 2005.

Aliphatic Polyesters

Nonproprietary Names

See Table I.

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, and e-hydroxycaproic acid. Typically, the molecular weights of homopolymers and copolymers range from 2000 to >100 000.

Structural Formula

 

Functional Category

Bioabsorbable; biocompatible; biodegradable material.

Applications in Pharmaceutical Formulation or Technology

Aliphatic polyesters are a group of synthesized, nontoxic, biodegradable polymers. In an aqueous environment, they undergo 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. Owing to their reputation as safe materials and their biodegradability, aliphatic polyesters are primarily used as biocompatible and biodegradable polymers for formulation of many types of implantable and injectable drug-delivery systems for both human and veterinary use. Examples of implantable drug delivery systems include rods, cylinders, tubing, films,(1) fibers,(2) pellets, and beads.(3) Examples of injectable drug-delivery systems include micro- capsules,(4) microspheres,(5) nanoparticles, and liquid injectable controlled-release systems. The rate of biodegradation and drug-release characteristics from these systems formulated with the aliphatic polyesters can be controlled by changing the physicochemical properties of the polymers, such as crystal- linity, hydrophobicity, monomer stereochemistry, copolymer ratio, and polymer molecular weight.

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 2000 to greater than 100 000.

Co-monomer ratios of lactic acid and glycolic acid 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 Table II.

Polymer composition and crystallinity play important roles in the solubility of these aliphatic polyesters. The crystalline homopolymers of glycolic acid are soluble only in strong solvents, such as hexafluoroisopropanol. The crystalline homopolymers of lactic acid also do not have good solubility in most organic solvents. However, amorphous polymers of DL- lactic acid and copolymers of lactic acid and glycolic acid with a low 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.

Table I: Chemical names and CAS registry numbers of the aliphatic polyesters.

 

Generic name Composition (%) Synonyms Trade name Manufacturer CAS name CAS number    

Lactide Glycolide Caprolactone    

Poly(D-lactide) 100 0 0 D-PLA Purasorb PD PURAC (3R-cis)-3,6-Dimethyl-1,4-dioxane-2,5-dione [25038-75-9]    

homopolymer    

Poly(L-lactide) 100 0 0 L-PLA Lactel L-PLA BPI Propanoic acid, 2-hydroxy-, homopolymer [26161-42-2]    

Medisorb 100 L Alkermes    

Purasorb PL PURAC    

Resomer L 206, 207, 209, 210, BI    

214    

Poly(DL-lactide) 100 0 0 DL-PLA Lactel DL-PLA BPI Propanoic acid, 2-hydroxy-, homopolymer [34346-01-5]    

Medisorb 100 DL Alkermes    

Pursasorb PDL PURAC    

Resomer R 202, 202H, 203, 206, BI    

207, 208    

Poly(glycolide) 0 100 0 PGA Lactel PGA BPI Acetic acid, hydroxy-, homopolymer [34346-01-5]    

Medisorb 100 PGA Alkermes    

Purasorb PG PURAC    

Resomer G 205 BI    

Poly(L-lactide-co-glycolide) 75 25 0 L-PLGA (75 : 25) Pursasorb PLG PURAC 1,4-Dioxane-2,5-dione, polymer with (3S-cis)- [30846-39-0]    

3,6-dimethyl-1,4-dioxane-2,5-dione    

Poly(L-lactide-co-glycolide) 50 50 0 L-PLGA (50 : 50) Purasorb PLG PURAC 1,4-Dioxane-2,5-dione,polymer with (3S-cis)-  [30846-39-0]    

3,6-dimethyl-1,4-dioxane-2,5-dione    

Poly(DL-lactide-co- 85 15 0 Polyglactin;DL-PLGA Lactel 8515 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with [26780-50-7]    

glycolide) (85:15) hydroxyacetic acid    

Medisorb 8515 DL Alkermes    

Resomer RG 858 BI    

Poly(DL-lactide-co- 75 25 0 Polyglactin;DL-PLGA Lactel 7525 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with [26780-50-7]    

glycolide) (75 : 25) hydroxyacetic acid    

Pursasorb PDLG PURAC    

Resomer RG 752, 755, 756 BI    

Poly(DL-lactide-co- 65 35 0 Polyglactin;DL-PLGA Lactel 6535 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with [26780-50-7]    

glycolide) (65 : 35) hydroxyacetic acid    

Poly(DL-lactide-co- 50 50 0 Polyglactin;DL-PLGA Lactel 5050 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with [26780-50-7]    

glycolide) (50 : 50) hydroxyacetic acid    

Medisorb 5050 DL Alkermes    

Purasorb PDLG PURAC    

Resomer RG 502, 502H, 503, BI    

503H, 504, 504H, 505, 506    

Poly-e-caprolactone 0 0 100 PCL Lactel PCL BPI 2-Oxepanone, homopolymer [24980-41-4]    

Poly(DL-lactide-co- 75 0 25 DL-PLCL (75 : 25) Lactel 7525 DL-PLCL BPI 1,4-Dioxane-2,5-dione,3,6-dimethyl-, [70524-20-8]    

caprolactone) polymer with 2-oxepanone    

Poly(DL-lactide-co- 25 0 75 DL-PLCL (25 : 75) Lactel 2575 DL-PLCL BPI 1,4-Dioxane-2,5-dione,3,6-dimethyl-, [70524-20-8]    

caprolactone) polymer with 2-oxepanone  

Alkermes, Alkermes Inc.; BI, Boehringer Ingelheim; BPI, Birmingham Polymers Inc.; PURAC, PURAC America.

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 80–150 000    

Inherent viscosity (mPa s) 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) 1.1–1.4(b) 0.7–1.3(c)    

Melting point (8C) Amorphous Amorphous Amorphous Amorphous Amorphous 173–178 225–230 58–63    

Glass transition (8C) 45–50 45–50 50–55 50–55 55–60 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(d) MeCl2, THF, EtOAc, MeCl2, THF, EtOAc, MeCl2, THF, EtOAc, MeCl2, THF, EtOAc, MeCl2, THF, EtOAc, MeCl2, CHCl3 HFIP, HFASH MeCl2, CHCl3,    

C3H6O, CHCl3 C3H6O, CHCl3 C3H6O, CHCl3 C3H6O, CHCl3, C3H6O, CHCl3 C3H6O    

Specific gravity 1.34 1.30 1.30 1.27 1.25 1.24 1.53 1.11    

Tensile strength (psi) 6000–8000 6000–8000 6000–8000 6000–8000 4000–6000 8000–12 000 10 000+ 3000–5000    

Elongation (%) 3–10 3–10 3–10 3–10 3–10 5–10 15–20 300–500    

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(lactic-co-glycolic acid); DL-PLA: DL-polylactic acid; L-PLA: L-polylactic acid; PGA: polyglycolic acid; PCL: poly-e-caprolactone.

(a) Specifications obtained from Birmingham Polymers, Inc.

(b) (HFIP) hexafluoroisopropanol.

(c) (CHCl3) chloroform.

(d) Partial listing only: MeCl2, methylene chloride; THF, tetrahydrofuran; EtOAc, ethyl acetate; HFIP, hexafluoroisopropanol; HFASH, hexafluoroacetone sesquihydrate; C3H6O, acetone.

Aliphatic Polyesters 27 

Stability and Storage Conditions

The aliphatic polyesters are easily susceptible to hydrolysis in the presence of moisture. Hence, they should be properly stored, preferably refrigerated at below 08C. It is necessary to allow the polymers to reach room temperature 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 poly- condensation of hydroxycarboxylic acids and catalytic ring- opening polymerization of lactones. Ring-opening polymeriza- tion is preferred because polyesters with high molecular weights can be produced. Moreover, the dehydration of hydroxycar- boxylic 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.

Safety

Poly(lactide), poly(glycolide), poly(lactide-co-glycolide), and polycaprolactone are used in parenteral pharmaceutical for- mulations 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 polyesters produce acid materials such as hydroxyacetic and/or lactic acid in the presence of moisture; thus, contact with materials that will react with acids, especially in moist conditions, should be avoided.

Regulatory Status

GRAS listed. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Lactic acid.

Comments

Due to their ability to form complexes with heavy metal ions, aliphatic polyesters are added to skin-protective ointments.(6)

Specific References

Jackanicz TM, Nash HA, Wise DL, Gregory JB. Polylactic acid as a biodegradable carrier for contraceptive steroids. Contraception 1973; 8: 227–233.

Eenink MJD, Feijen J, Olijslager J, et al. In: Anderson JM, Kim SW, eds. Advances in Drug Delivery Systems. Amsterdam: Elsevier: 1987: 225–247.



Schwope AD, Wise DL, Howes JF. Lactic/glycolic acid polymers as narcotic antagonist delivery system. Life Sci 1975; 17: 1877–1886.

4 Juni K, Ogata J, Nakano M, et al. Preparation and evaluation in vitro and in vivo of polylactic acid microspheres containing doxorubicin. Chem Pharm Bull 1985; 33(1): 313–318.

Sanders LM, Burns R, Bitale K, Hoffman P. Clinical performance of nafarelin controlled release injectable: influence of formulation parameters on release kinetics and duration of efficacy. Proc Int Symp Control Rel Bioact Mater 1988; 15: 62–63.

Hoeffner EM, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th edn. Munich, Germany: Editio Cantor Verlag Aulendorf, 2002: 1270.

General References

Barrows T. Degradable implant materials: a review of synthetic absorbable polymers and their applications. Clin Mater 1986; 1: 233–257.

Chu CC. An in-vitro study of the effect of buffer on the degradation of poly (glycolide) sutures. J Biomed Mater Res 1981; 15: 19–27.

Chu CC. The effect of pH on the in vitro degradation of poly (glycolide lactide) copolymer absorbable sutures. J Biomed Mater Res 1982; 16: 117–124.

Danckwerts M, Fassihi A. Implantable controlled release drug delivery systems: a review. Drug Dev Ind Pharm 1991; 17(11): 1465–1502. Gilding DK, Reed AM. Biodegradable polymers for use in surgery- polyglycolic/poly(lactic acid) homo- and copolymers: 1. Polymer

1979; 20: 1459–1464.

Kissel T, Li YX, Volland C. Properties of block- and random- copolymers of lactic acid and glycolic acid. Proc Int Symp Control Rel Bioact Mater 1993; 20: 127–128.

Kitchell JP, Wise DL. Poly(lactic/glycolic acid) biodegradable drug- polymer matrix systems. Methods Enzymol 1985; 112: 436–448.

Kulkarni RK, Moore EG, Hegyeli AF, Leonard F. Biodegradable poly(lactic acid) polymers. J Biomed Mater Res 1971; 5: 169–181. Lewis H. Controlled release of bioactive agents from lactide/glycolide polymers. In: Chasin M, Langer R, eds. Biodegradable Polymers as

Drug Delivery Systems. New York: Marcel Dekker, 1990: 1–41.

Li SM, Garreau H, Vert M. 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: 130–139.

Nguyen TH, Higuchi T, Himmelstein J. Erosion characteristics of catalyzed poly(orthoester) matrices. J Controlled Release 1987; 5: 1–12.

Pitt CG, Gratzl MM, Jeffcoat AR, et al. Sustained drug delivery systems II: factors affecting release rates from poly (e-caprolactone) and related biodegradable polyesters. J Pharm Sci 1979; 68(12): 1534–

1538.

Reed AM, Gilding DK. Biodegradable polymers for use in surgery- poly(glycolic)/poly(lactic acid) homo and copolymers: 2. In vitro degradation. Polymer 1981; 22: 494–498.

Shah SS, Cha Y, Pitt CG. Poly(glycolic acid-co-dl lactic acid): diffusion or degradation controlled drug delivery? J Controlled Release 1992; 18: 261–270.

Vert M, Li S, Garreau H. New insights on the degradation of bioresorbable polymeric devices based on lactic and glycolic acids. Clin Mater 1992; 10: 3–8.

Visscher GE, Robison RL, Maulding HV, et al. Biodegradation and tissue reaction to 50 : 50 poly(dl-lactide-co-glycolide) microcap- sules. J Biomed Mater Res 1985; 19: 349–365.

Williams DF. Mechanisms of biodegradation of implantable polymers.

Clin Mater 1992; 10: 9–12.

Authors

RK Chang, AJ Shukla, Y Sun.

Date of Revision

26 August 2005.

Alitame

Nonproprietary Names

None adopted.

Synonyms

Aclame; L-aspartyl-D-alanine-N-(2,2,4,4-tetramethylthietan-3- yl)amide; 3-(L-aspartyl-D-alaninamido)-2,2,4,4-tetramethyl- thietane.

Chemical Name and CAS Registry Number

L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanin-

amide anhydrous [80863-62-3]

L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanin-

amide hydrate [99016-42-9]

Empirical Formula and Molecular Weight

Isoelectric point: pH 5.6 Melting point: 136–1478C Solubility: see Table I.

Table I: Solubility of alitame.

Solvent Solubility at 208C unless otherwise stated

Chloroform 1 in 5000 at 258C

Ethanol 1 in 1.6 at 258C

n-Heptane Practically insoluble

Methanol 1 in 2.4 at 258C

Propylene glycol 1 in 1.9 at 258C

Water 1 in 8.3 at 58C

1 in 7.6 at 258C

1 in 3.3 at 408C

1 in 2.0 at 508C

C14H25N3O4S

1

331.44 (for anhydrous)

Specific rotation [a]25: +408 to +508 (1% w/v aqueous

C14H25N3O4S·2 /2H2O 376.50 (for hydrate)

Structural Formula

 

Functional Category

Sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Alitame is an intense sweetening agent developed in the early 1980s and is approximately 2000 times sweeter than sucrose. It has an insignificant energy contribution of 6 kJ (1.4 kcal) per gram of alitame.

Alitame is currently primarily used in a wide range of foods and beverages at a maximum level of 40–300 mg/kg.(1)

Description

Alitame is a white nonhygroscopic crystalline powder; odorless or having a slight characteristic odor.

Pharmacopeial Specifications