Polysaccharides for Drug Delivery and Pharmaceutical Applications

Chapter 6

Downloaded by UNIV OF TENNESSEE KNOXVILLE on December 21, 2014 | http://pubs.acs.org Publication Date: June 22, 2006 | doi: 10.1021/bk-2006-0934.ch006

Cross-Linked Starch Derivatives for Highly Loaded Pharmaceutical Formulations MirceaAlexandruMateescu, Pompilia Ispas-Szabo, and Jérôme Mulhbacher Department of Chemistry and Biochemistry, Université du Québec à Montréal, C.P. 8888, Succ. A, Montréal, Québec H3C 3P8, Canada

Starch derivatives were obtained from Crosslinked High Amylose Starch (HASCL) by substitution with Carboxymethyl (CM-), Aminoethyl (AE-) or Acetate (Ac-) groups. The new polymers are able to generate ionic or neutral networks involved in the control of drug release. Surprisingly, it was found that the drug loading capacity of the new derivatives was markedlly higher compared to the unsubstituted H A S C L . The H A S C L derivatives ensured a close to linear release for 16-24h and they were proposed as excipients for oral solid dosage forms. Dissolution kinetics and mechanistic studies (related to swelling and diffusion aspects) allowed a better understanding of the physical and molecular phenomena controling the drug delivery from these novel matrices.

© 2006 American Chemical Society

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In Polysaccharides for Drug Delivery and Pharmaceutical Applications; Marchessault, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.


122 Starch modification by crosslinking was first aimed to prevent its rétrogradation (1) contributing thus to the stabilization of the amylaceous preparations used in the food industry. Crosslinked high amylose starch (HASCL), a hybrid plant product was suggested in the late seventies as a material for size-exclusion chromatography (2) and as a specific stationary phase for affinity chromatography separation of alpha amylase (3) and haemoglobin (4) as well as for specific retention of macrophage cells (5). Although crosslinked, the H A S C L still remains a substrate of alpha-amylase, with the mention that the rate of amylolysis decreases with the increase of the crosslinking degree (6). This led to the use of CrossLinked (CL)-Amylose as substrate for selective and fast determination of alpha-amylase (6,7). Formulated as a tablet test (Iodocrom®), it allowed a fast (5-10 min), single step diagnostic of acute pancreatitis (8). Carboxymethyl (CM-) and diethylaminoethyl (DEAE-) crosslinked high amylose starch were proposed, also in the late seventies, as chromatographic materials for biochemical separations (9). Ten years later, in the early nineties, cross-linked high amylose starch was introduced as an excipient with a high potential for pharmaceutical formulation of many therapeutical molecules (12). A particular feature of H A S C L , was the non-monotonous dependency of the drug release times with increasing crosslinking degree (eld). At high cross-linking, the hydration is so strong that the material acts as a powerful disintegrant - Liamid® (15-16). Under the same treatment conditions, when the polymer is subjected only to physical treatment (gelatinization, drying) without chemical reticulation, the uncross-linked high amylose starch was found to generate a faster release, caused by the tablet capping and final disintegration. Maximal release time was obtained for a narrow interval of low eld, whereas at high crosslinking, a fast decrease of release time was found. Considering the percentage of crosslinker used to react with 100 g of polymer as a conventional crosslinking degree, the best drug release time in vitro was obtained for H A S C L - 6 (10). This particular behaviour (11,13,14) can be explained by the fact that only a low eld will allow enough chain flexibility for self-assembling and stabilization by physical forces, mostly, hydrogen bonding.

Abbreviations: C M - H A S C L - 6 , carboxymethyl high amylose starch cross-linked 6*; A E - H A S C L - 6 , aminoethyl high amylose starch cross-linked 6*; A c - H A S C L 6, acetate high amylose starch cross-linked 6*; *cld, cross-linking degree (expressed in grams of bifiinctional agent used to cross-link 100 g of polymers).


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These structural aspects induce the formation of the matrix which, in fact, controls the drug release. At higher eld this self-stabilization by hydrogen bonding is hindered and hydroxyl groups are free to hydrate and trigger the polymer swelling. The H A S C L behaves as a hydrogel at low cross-linking and the drug liberation is governed by swelling only or by swelling and diffusion mechanisms. This control was found for a drug loading of 20% or moderately higher while at a loading higher than 30 %, the control of the release is lost and tablets loose their integrity. As mentioned before, despite crosslinking, the H A S C L excipient is still susceptible to alpha-amylase action. This behavior led to a new concept known as Enzymatically Controlled Drug Release (ECDR), applicable for drugs exhibiting particularly long release times or incomplete releases (i.e. due to the drug low solubility or to interactions with starch matrices). The drug liberation can be accelerated by an enzymatically-controlled release, based on the addition of alpha-amylase to the formulation (17,18). During the last decade, we developed a new series of crosslinked high amylose starch obtained by further derivatization through carboxymethylation, aminoethylation and acetylation (19,20). The first reason for derivatization was to reduce the susceptibility of H A S C L to intestinal amylolysis which improves the tablet stability and the drug release time. Surprisingly, it was found that the drug loading capacity was markedly higher compared to the unsubstituted H A S C L . It is worth noting also , a lower susceptibility (21) to alpha-amylase attack of the polymeric derivatives. We are now reviewing these new series of crosslinked starch derivatives, discussing their high loading capacity and several mechanistic aspects allowing a better understanding of the processes controlling the drug release from these novel matrices.

Derivatization of crosslinked high amylose starch It was of interest to follow the behavior of H A S C L derivatized with cationic, anionic or less polar groups, and to correlate the matrix modification with their release control properties and to evaluate possible interactions with


124 charged and uncharged drugs. Can these modified matrices modulate the release of drugs through their polar (positive or negative) or non polar global groups and can they generate a slower release, particularly in formulations with a high drug


loading? (22,23). Hydroxyl groups were shown to play an important role in the organization of the network and consequently in the control of the drug release (10-11). In terms of interacting forces, the carboxylic or amino groups present in C M - and A E - starch derivatives can be involved, for instance, in new hydrogen bonds with the hydroxyl groups of the matrix. On the other hand, the drug characteristics (i.e. molecular size, conformation, ionization, etc.) can affect its diffusion through the matrix. When the gel and the drug are ionized, attracting or repelling forces between them will increase or decrease the diffusion rate. For the present studies, three types of derivatives were synthesized from H A S C L - 6 by substitution of hydroxylic groups with cationic (carboxymethyl: C M ) , anionic (aminoethyl: A E ) or less polar acetate (Ac) groups (Scheme I). Synthesis of CM-HASCL-6 - was realized as described by Mulhbacher et al. (19). After neutralization and washing the remaining wet gel paste was finally dried with pure acetone to obtain the C M - H A S C L in powder form.

CM-HASCL

- O- CH 2

- o- (CH ) -NH

h OH

HASCL

2

- •

2

Γ" 0-CO-CH

NH -HASCL 2

2

Ac-HASCL 3

Scheme I. Schematical presentation of High Amylose Starch and its derivatives.

Synthesis ofAE-HASCL-6: The single-step procedure was almost the same as for C M - H A S C L , with the mention that the H A S was first crosslinked and then derivatized with 85 g of


125 chloroethylamine AE-HASCL.

hydrochloride (9)

at a pH between 9 and 10, to generate

Synthesis ofAc-HASCL-6:


The one step procedure was similar to that for C M - H A S C L - 6 , with crosslinking and then treatment with 142 mL of acetic anhydride (9) to yield the A c H A S C L derivatives. For all derivatives here presented, the degree of substitution can be varied by using different ratios of : substitution reagent / H A S C L polymer.

Controlled release properties and dissolution kinetics It was shown that these new polymeric excipients were able to control the release over 20 h from monolithic tablets loaded with 20 to 60% (w/w) drug. Using different drugs as model tracers, such as Acetaminophen (uncharged molecule), Acetylsalicylic acid (carrying acidic group) and Metformin (carrying a basic group), it was found that the release of the ionic drugs from ionic polymeric matrices ( C M - H A S C L and A E - H A S C L ) could be partially controlled via the ionic interaction established between pendant groups of polymeric matrix and drugs. The substitution degree of H A S C L derivatives can also be varied in order to modulate the release time (19) of the drug. At 20% acetaminophen loading, no major differences between release times from various derivatives were found (Fig. la). For all tested formulations, the release time was estimated as the duration required for 90% of drug to be released in to receiving media, (phosphate buffer 0.05M at pH 7). At higher acetaminophen loading (40% and 60% drug), the C M - H A S C L , A E - H A S C L and A c - H A S C L derivatives were able to control the release over 16 to 22 h, while for tablets based on non-modified H A S C L , 90% release time was much lower: only 2-6 h (Fig. lb,c). No erosion, no sticking and no flotation of the tabletsbased on derivativzed H A S C L were observed during the dissolution tests (19). Despite the common trend of all derivatives to provide a good control for 16 to 22 h, their general behavior during drug dissolution was different from one derivative to another. The C M - H A S C L exhibited a significant swelling capacity where the carboxylic groups possibly play a role, modulating the water access and contributing thus to the drug release. The A E - H A S C L tablets have shown remarkable mechanical properties during drug release and less swelling capacity. The amino groups are probably involved in hydrogen bonding, enhancing thus tablet stability and controlling the drug release through a more compact structure. The A c - H A S C L derivatives contained less polar acetate groups and weaker hydrogen stabilisation, but exhibited also good mechanical properties.



126

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•

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1

Ο

5

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35

25

30

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Time (h)

0

5

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Time (h)

Figure 1: The release of acetaminophen from tablets based on HASCL-6 and derivatives, containing 20% (a), 40% (b) and 60% (c) drug (from Mulhbacher et al, J. Control Release 2001, with permission).


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Longer release times from A c - H A S C L tablets can be explained in this case by a limited water access into the matrix due to the less hydrophilic character of the polymeric excipient. Acetyl-salicylic acid formulated in highly loaded dosages with the ionic ( C M - H A S C L or A E - H A S C L ) or with the less polar (Ac-HASCL) matrices clearly generates longer release times than highly loaded of Metformin (containing amino function), for which only the C M - H A S C L matrix allowed longer release times (19). It should be noted that Metformin is a highly soluble (chlorohydrate) molecule and that the required daily dosagee is high enough (approx. lg). C M - H A S C L can be therefore, an excipient of choice for Metformin slow-release. In an attempt to elucidate if A E - H A S C L and C M - H A S C L matrices could exert ionic interactions with incorporated drugs and thus modulate their release, additional dissolution tests were conducted with two model molecules: phenylacetic acid (136 Da) and benzylamine (107 Da) having similar molecular size and conformation, except the ionic groups: carboxyl in the first case and amino for the second. Data from Table I clearly indicate that ionic interactions exist between A E - H A S C L (with amino groups) and Phenylacetic acid (with a relatively strong carboxylic group) giving longest release (24h). Similar interactions occur between C M - H A S C L (with carboxylic groups) and Benzylamine (with a basic amino group) yielding longest release (24h).

Table 1: The influence of charged drugs on the 70% and 90% dissolution times from neutral, anionic and cationic H A S C L - 6 derivative matrices.

Matrices Ac-HASCL-6 AE-HASCL-6 CM-HASCL-6

Benzylamine Release time (h)

Phenylacetic acid Release time (h)

70%

90%

70 %

90%

4 4 10

9

8 15 10

17 24 18

10 23

In fact, the C M - H A S C L generated a 90% release time of 23 h for benzylamine and 18 hours for phenylacetic acid whereas with A E - H A S C L the 90% release time was about 24 hours for phenylacetic acid and only 10 hours for benzylamine. The A c - H A S C L , with no ionic charges (considered as control) generated 9 hours for benzylamine and of 17 hours for phenylacetic acid. The substitution degree appears to have an important effect on the release time. For the three tracers, the 90% release times from the C M - H A S C L and A c -


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H A S C L tablets increase when the substitution degrees increase, and this for each drug loading (20, 40 and 60%). in the case of tablets based on A E - H A S C L , release kinetics of Acetaminophen and Metformin are similar to thosefromC M and A c - derivatives. In the case of Acetyl-salicylic acid tracer, a higher substitution degree of A E - H A S C L generates longer release times (19). Unexpectedly, the dissolution of Acetylsalicylic acid (Fig. 2), was longest at higher drug loading (normally higher loading generates a faster release). This behavior suggests an interaction of Acetyl salicylic acid with the C M - H A S C L - 6 matrix. In conclusion, each type of derivative can generate optimal release times for each of the drugs tested. The A c - H A S C L allows the best release time for Acetaminophen that is the less polar drug tested. The A E - H A S C L induced the longest release time for Aspirin (carboxylic groups) and C M - H A S C L ensured the longest release for Metformin (amino groups). Therefore, the release control of the ionic drugs from C M - H A S C L and A E - H A S C L matrices could be modulated by ionic interaction. Furthermore, all H A S C L derivatives represent novel excipients allowing a good control of the release of drugs from high dosage formulations. For each type of drug, there can be an optimal choice of polymeric starch derivative that generates the best release time as a function of its molecular characteristics.

Mechanistic studies I. Swelling properties Aspects of the swelling properties of H A S C L , C M - H A S C L , A E - H A S C L and A c - H A S C L matrices in relation with the pH and ionic strength of the dissolution media were recently reported (25) and largely discussed in terms of equilibrium swelling ratio, swelling velocity and values of η exponent, as defined by Khare and Peppas (22). The equilibrium swelling ratio for H A S C L and A c H A S C L after 24h were the lowest, followed in increasing order by those of A E H A S C L and C M - H A S C L (Fig. 3a). The swelling ratio of the C M - derivative was the highest. The A c - derivative and H A S C L presented almost the same swelling ratio, despite the fact that the acetyl groups are less polar and, in addition, can hinder the hydrogen association of the amylose, creating thus some amorphous region in the matrix which could be filled and swollen by water. Higher equilibrium swelling ratio values were found for A E - and CM» derivatives with more hydrophilic functional groups. The swelling ratio of the H A S C L and its A c - and A E - derivatives did not change with the p H increase from 1.2 (gastric) to 7 (intestinal), whereas for C M - H A S C L the swelling was p H dependent, markedly increasing with pH increase (Fig 3a). The swelling ratio of each polymeric material increased at pH 10 (Fig. 3a), probably due to the fact that hydroxyl groups of high amylose starch and derivatives, still involved in hydrogen bonds (chain-chain) at pH 1-7, begin to be deprotonated at values between pH 7-10.


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Acetylsalicylic add loading (°/

Polysaccharides for Drug Delivery and Pharmaceutical Applications

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