In-situ gel formation of pectin

Details In-situ gel formation of pectin In-situ gel formation of pectin

2001-02-28

2004-08-17

Nguyen, Dave T. (Department: 1635)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C514S001000, C514S002600, C514S04400A, C514S157000

Reexamination Certificate

active

06777000

ABSTRACT:

BACKGROUND
The present invention relates to in-situ gelation of a pectic substance. Specifically, the invention relates to a pectin in-situ gelling formulation for the delivery and sustained release of a physiologically active agent to the body of an animal. More specifically, the pectic substance is derived from Aloe vera L. plant.
Abbreviations Used Herein Include:
CMC, carboxylmethyl cellulose; Da, dalton; DM, degree of methylation; Gal A, galacturonic acid; HEC, hydroxyethyl cellulose; HM, high methoxyl; HPMC, hydroxypropylmethylcellulose; kDa, kilodaltons; LM, low methoxyl; PBS, phosphate buffered saline; PEG-PLGA-PEG, polyethylene glycol-poly(lactic-co-glycolic acid)-polyethylene glycol; PEO-PLLA, poly(ethylene oxide)-poly(L-lactide); PEO-PPO-PEO, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide).
Pectin is a biodegradable acidic carbohydrate polymer. Pectin is commonly found in plant cell walls. The cell wall of a plant is divided into three layers consisting of the middle lamella, the primary wall and the secondary cell wall. The middle lamella is richest in pectin. The chemistry and biology of pectin have been extensively reviewed (Pilnik and Voragen,
Advances in plant biochemistry and biotechnology
1, 219-270, 1992; Voragen et al,
In Food polysaccharides and their applications
. pp 287-339. Marcel Dekker, Inc. New York, 1995; Schols and Voragen,
In Progress in Biotechnology
14.
Pectins and pectinases
, J. Visser and A. G. J. Voragen (eds.). pp. 3-20. Elsevier Science Publishers B. V. Amsterdam, 1996).
Pectin consists of an &agr;-(1→4)-linked polygalacturonic acid backbone intervened by rhamnose residues and modified with neutral sugar side chains and non-sugar components such as methyl and acetyl groups. The extent of rhamnose insertions and other modifications vary depending on plant sources. The Gal A content is generally more than 70% whereas the rhamnose content is typically <2%. Rhamnose residues are &agr;-(1→2)-linked to Gal A residues in the backbone. They cause the formation of a T-shaped kink in the backbone chain, and the increase in rhamnose content leads to more flexible molecules. The neutral sugar side chains are attached to the rhamnose residues in the backbone at the O-3 or O-4 position. The rhamnose residues tend to cluster together on the backbone. Hence, this region with side chains attached is referred to as the “hairy region” while the rest of the backbone is named the “smooth region.”
Methylation occurs at carboxyl groups of Gal A residues. The degree of methylation or methyl-esterification (“DM”) is defined as the percentage of carboxyl groups (Gal A residues) esterified with methanol. Based on the DM, pectins are divided into two classes, low methoxyl (“LM”) pectin with a DM of <50% and a high methoxyl (“HM”) pectin with a DM of >50%. Commercial pectins derived from citrus and apples are naturally HM pectins. LM pectins are typically obtained through a chemical de-esterification process. Commercial LM pectins typically have a DM of 20-50%. A completely de-esterified pectin is referred as “pectic acid” or “polygalacturonic acid”. Pectic acid in the acid form is insoluble but is soluble in the salt form. The common salt form of pectic acid is either sodium or potassium.
Pectin is most stable at acidic pH levels between approximately 3-4. Below pH 3, methoxyl and acetyl groups and neutral sugar side chains are removed. Under neutral and alkaline conditions, methyl ester groups are saponified and the polygalacturonan backbone breaks through &bgr;-elimination-cleavage of glycosidic bonds on the non-reducing ends of methylated Gal A residues. Pectic acids and LM pectins are relatively more resistant to neutral and alkaline conditions since there are only limited numbers of methyl ester groups or none at all.
Current commercial pectins are mainly from citrus and apples. However, besides citrus and apples, pectins can also be isolated from many other plants. All vegetables and fruits that have been examined contain pectins. Pectins from sugar beets, sunflowers, potatoes, and grapefruits are just a few other well known examples.
Both HM and LM pectins form gels. However, these gels form via totally different mechanisms (Voragen et al,
In Food polysaccharides and their applications
. pp 287-339. Marcel Dekker, Inc. New York, 1995). HM pectin forms a gel in the presence of high concentrations of co-solutes (sucrose) at low pH. LM pectin forms a gel in the presence of calcium, thus, it is “calcium-reactive.” The calcium-LM pectin gel network is built by formation of what is commonly referred to as an “egg-box” junction zone in which Ca++ causes the cross-linking of two stretches of polygalacturonic acid chains.
HM pectins are generally not reactive with calcium ions and therefore cannot form a calcium gel. However, certain HM pectins have been reported to be calcium sensitive and capable of calcium gel formation. In addition, HM pectins can be made calcium-reactive by a block wise de-esterification process while still having a DM of >50%. See, Christensen et al. U.S. Pat. No. 6,083,540.
Calcium-LM pectin gel formation is influenced by several factors, including DM, ionic strength, pH, and molecular weight (Garnier et al.,
Carbohydrate Research
240, 219-232, 1993; 256, 71-81, 1994). The lower the DM and the higher the molecular weight, the more efficient the gelation. Furthermore, the calcium-LM pectin gelation is more efficient at a neutral pH of ~7.0 than ~3.5. Lastly, the addition of monovalent counter ion (NaCl) enhances the gelation, i.e., less calcium is required for gel formation.
Pectins are typically utilized in the food industry and classified by the FDA as “GRAS” (Generally Regarded As Safe). They have also long been used as colloidal and anti-diarrhea agents. Recently, pectins have been utilized in the areas of medical device and drug delivery (Thakur et al.,
Critical Reviews in Food Science & Nutrition
37, 47-73, 1997). In the case of drug delivery, pectin has found its presence in many experimental formulations for oral drug delivery to the colon because pectin is readily degraded by bacteria present in this region of the intestines. The pectin is either used directly with no gelation involved or a pectin calcium gel is preformed to encapsulate the drug agent before administration. Ashford et al.,
J. Controlled Release
26, 213-220, 1993; 30, 225-232, 1994; Munjeri et al.,
J. Controlled Release
46, 273-278, 1997; Wakerly et al.,
J. Pharmacy & Pharmacology
49, 622-625, 1997;
International Journal of Pharmaceutics
153,219-224,1997; Miyazaki et al.,
International Journal of Pharmaceutics
204, 127-132, 2000. Prior to the present invention, there appears to be no attempt made to examine the in-situ gelling ability of pectins.
Aloe pectin isolated from Aloe vera plant as described in U.S. Pat. No. 5,929,051, the entire content of which is incorporated herein by reference. It is naturally a LM pectin and capable of calcium gelation. In addition, it possesses several unique chemical properties that are particularly related to gelation, including a high molecular weight (>1×10
6
Da), a high Gal A content (as high as >90%), and a low DM (<10%).
Current commercial pectins typically have a size of 7-14×10
4
Da and Gal A content of ~75% (Voragen et al,
In Food polysaccharides and their applications
. pp 287-339. Marcel Dekker, Inc. New York, 1995). These pectins have a rhamnose content of <2%. Commercial LM pectins and other natural LM pectins have a DM of >20%. A DM below 10% makes Aloe pectin nearly a pectic acid. A pectin with such a low DM, a high molecular weight, and a high Gal A content has not been described previously. Aloe pectin is an off white powder as the finished product, whereas all current commercial and experimental pectins are yellow to tan powders.
Drug delivery has been a subject of intense studies over recent years. The goal is to achieve sustained (or slow) and/or controlled drug release and thereby improve efficacy, safety, and/or patie

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