Excipient poly polymers

Poly(ortho esters) were first developed by the ALZA corporation (Alzamer) in 1970 in order to seek new synthetic polymer for drug delivery applications. These polymers degrade by surface erosion and degradation rates may be controlled by incorporation of acidic or basic excipients. The polymer is hydrophobic enough such that its erosion in aqueous environments is very slow. The unique features of poly(ortho esters), in addition to their surface erosion mechanism, is the rate of degradation for these polymers, pH sensitivity, and glass transition temperatures, which... 

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

Initial work with poly (ortho esters) focused on norethindrone and the use of water-soluble excipients such as Na2C03, NaCl, and Na2S04 (27). As described by Fedors (28), the inclusion of such water-soluble salts leads to an osmotically driven water intake into the polymer. This water intake leads to polymer swelling with consequent release of the incorporated norethindrone. The effect of incorporated NaCl and Na2C03 on erosion rate as compared to the... 

Type IV poly(ortho esters) are very similar in structure to type II poly(ortho esters), but they do not need to have excipients in the formulation due to the incorporation of no acidic moieties in the polymer backbone (Ng et al. 1997). Rods of poly(ortho ester) loaded with recombinant human-growth hormone and bovine serum albumin have been created. The rods are the products of polymer-protein mixture extrusion at a temperature between 50° and 70°C. Particles have also been produced from these rods (Heller et al. 2000). The size of these particles, >106 pm, was much larger than would be expected to be absorbed by the gastrointestinal lining (Florence 1997). If the particle size can be reduced, this type of polymer system may be made to be acceptable for oral administration. 

Poly(ortho esters) offer the advantage of controlling the rate of hydrolysis of acid-labile linkages in the backbone by means of acidic or basic excipients physically incorporated in the matrix. This results in polymer degradation proceeding purely by surface erosion, which results in zero-order drag release from disk-shaped devices. 

Several polymers were found to fit all or most of the above criteria and were used to prepare the carrier films. Many polymers have been used for this purpose, viz., ethyl cellulose, poly(y-benzyl glutamate), poly(vinyl acetate), cellulose acetate phthalate, and the copolymer of methyl vinyl ether with maleic anhydride. In addition to the base polymers, plasticizers were often needed to impart a suitable degree of flexibility. Plasticizers, which are found to be compatible with polymeric materials include, acetylated monoglycerides, esters of phthalic acid such as dibutyl tartarate, etc. An excipient was usually incorporated into the matrix of the carrier films. The excipients used were water-soluble materials, which are capable of creating channels in the polymer matrix and facilitate diffusion of the drug. PEGs of different molecular weights were used for this purpose. 

Research on nasal powder drug delivery has employed polymers such as starch, dextrans, polyacrylic acid derivatives (e.g., carbopol, polycarbophil), cellulose derivatives (microcrystalline cellulose, semicrystalline cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose), chitosan, sodium alginate, hyaluronans, and polyanhydrides such as poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). Many of these polymers have already been used as excipients in pharmaceutical formulations and are often referred to as first-generation bioadhesives [38-45], In nasal dry powder a single bioadhesive polymer or a... 

Similar behavior has been observed for noncrystallizing polymers. For example, the diffusivity of water in poly(vinylpyrrolidone) (PVP) (Oksanen and Zografi, 1993) has been shown to increase at water contents beyond the hydration limit. Additional reports have shovm that the hydration limit has physical significance for other polymer excipients. Microcrystalline cellulose and lactose for compression, for example, lose their direct compaction properties at water contents just below (Huettenrauch and Jacob, 1977), and gelatin capsules become brittle as the water content is reduced below Wm (Kontny and Mulski, 1989). Recently, the chemical stability of a model peptide in PVP matrices was shown to improve when the amorphous dispersion was stored below the polymer s hydration limit (Lai et al., 1999a Lai et al., 1999b Lechuga-Ballesteros et al., 2002). 

Even though the hydrolysis eventually produces an acid, polymer erosion rate is controlled by hydrolysis of the ortho ester bonds. The subsequent hydrolysis of the ester bonds takes place at a much slower rate so that the neutral, low molecular weight reaction products can diffuse away from the implant before hydrolysis to an acid takes place. Thus, unlike the poly (ortho ester) system I, no autocatalysis is observed and it is not necessary to use basic excipients to neutralize the acidic hydrolysis products. 

Use of basic excipients. As discussed in Sect. 4.2.4, a typical poly(ortho ester) device will be completely permeated by water in a matter of a few weeks so that the use of acidic excipients is limited to delivery systems having a maximum lifetime of about one month. However, ortho ester linkages are stable in devices containing a base, and very long erosion times are possible if the polymer is stabilized with a base which prevents hydrolysis even though the matrix is completely permeated by water. A plausible mechanism for erosion of devices that contain the base Mg(OH)2 is shown in Fig. 18. According to this mech-... 

In the initial approach, and before the action of acidic excipients was clearly understood, the slightly acidic and relatively water insoluble salt, calcium lactate, was used with the hopes of catalyzing long term surface erosion of linear poly (ortho esters). In this work, rod-shaped devices were prepared by incorporating 30 wt% levonorgestrei and 2 wt% calcium lactate into a polymer prepared from 3,9-bis (ethylidene-2,4,8,10-tetraoxaspiro [5,5] undecane) and a 60/40 mol mixture of trans-cyclohexane dimethanol and 1,6-hexanediol and the devices were implanted into rabbits. The devices were then explanted at various time intervals and examined by scanning electron microscopy. A device ex-planted after 10 weeks is shown in Fig. 27 [25]. 

Poly(ortho ester)s were the first polymers used to prepare surface eroding devices, but additional excipients such as acid anhydrides or basic excipients in the interior of the matrix, had to be used to prevent bulk erosion [79, 81]. 

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