**6.** *In situ* **forming implants**

The classic medicated implants are the bodies of the solid state and of a defined shape, which are administered by an invasive surgical intervention into the muscular or other tissue. Their implantation requires local anaesthesia and a surgical intervention. *In situ* forming implants (ISFI) are liquid systems with a relatively low viscosity administered by an injection needle or a trocar containing a substance or several substances, which in the site of administration due to the biological environment spontaneously change its or their properties, in particular the mechanical ones. An important parameter is easy elimination capacity of systems based either on their biodegradability or slow dissolution (Hatefi & Amsden, 2002). The systems contain an active ingredient which is released from such implants in a long-term period, in the order of weeks to months. It thus enhances the effect of active ingredients, with decreased fluctuation of plasma concentrations toxicity is decreased, with decreased frequency of dosing the compliance of the patient is increased. Besides easy administration, an advantage of this relatively new dosage form is its simple manufacture. The systems find their use in human medicine, veterinary medicine (Winzenburg et al., 2004), and tissue engineering (Quaglia, 2008).

ISFI are suitable for both local and systemic administration of substances with antimicrobial activity, antitumor substances, hormones, substances interacting with the immunity system, growth factors, etc. The importance of this mode of administration will be increased with the introduction of other medicinal substances of the protein type, as the structure of the implant can protect these substances against their enzymatic decomposition.

The first system is named Atrigel Technology® and was patented in 1990 (Dunn et al., 1990; Warren et al., 2009). It is based on the administration of solutions of biodegradable polymers into the soft tissue. After administration, the water-soluble solvent is distributed into the surrounding tissue and the polymer is precipitated due to a backflow of aqueous solutions from the biological environment. The development of implants was studied *in vivo* using a non-invasive ultrasound imaging technique. The release of the active ingredient from implants has been demonstrated to be influenced not only by the composition of the surrounding pathologically changed tissue, but also by the mechanical conditions in it (Patel et al., 2010), and the process of precipitation of the polymer is considerably influenced by its molecular mass (Solorio et al., 2010). A system with continuous release of the immunoenhancer thymosin alpha 1 was constructed by dispersion of chitosan or albumin microparticles with this substance in the poly(lactide-co-glycolide) matrices dissolved in N-methyl-2-pyrrolidone. This achieved thymosin release for a period of 15 to 30 days (Liu et al., 2010).

The problem of the system Atrigel Technology® is the toxicity of solvents and a sudden initial release of a substantial part of the total dose of the contained active ingredient. In

The matrix system containing a plasticized polymer can be also prepared by coating the pellets with a plasticized polymer and their subsequent compression to form tablets (Abdul et al., 2010). The use of a plasticizer does not require a curing step, which is heating after preparation. Pellets without a plasticizer are very brittle and break on compression. After an addition of 10 % triethyl citrate to the polymer Kollicoat SR30D (aqueous colloidal dispersion of polyvinyl acetate) the flexibility of the material was dramatically improved

The classic medicated implants are the bodies of the solid state and of a defined shape, which are administered by an invasive surgical intervention into the muscular or other tissue. Their implantation requires local anaesthesia and a surgical intervention. *In situ* forming implants (ISFI) are liquid systems with a relatively low viscosity administered by an injection needle or a trocar containing a substance or several substances, which in the site of administration due to the biological environment spontaneously change its or their properties, in particular the mechanical ones. An important parameter is easy elimination capacity of systems based either on their biodegradability or slow dissolution (Hatefi & Amsden, 2002). The systems contain an active ingredient which is released from such implants in a long-term period, in the order of weeks to months. It thus enhances the effect of active ingredients, with decreased fluctuation of plasma concentrations toxicity is decreased, with decreased frequency of dosing the compliance of the patient is increased. Besides easy administration, an advantage of this relatively new dosage form is its simple manufacture. The systems find their use in human medicine, veterinary medicine

ISFI are suitable for both local and systemic administration of substances with antimicrobial activity, antitumor substances, hormones, substances interacting with the immunity system, growth factors, etc. The importance of this mode of administration will be increased with the introduction of other medicinal substances of the protein type, as the structure of the

The first system is named Atrigel Technology® and was patented in 1990 (Dunn et al., 1990; Warren et al., 2009). It is based on the administration of solutions of biodegradable polymers into the soft tissue. After administration, the water-soluble solvent is distributed into the surrounding tissue and the polymer is precipitated due to a backflow of aqueous solutions from the biological environment. The development of implants was studied *in vivo* using a non-invasive ultrasound imaging technique. The release of the active ingredient from implants has been demonstrated to be influenced not only by the composition of the surrounding pathologically changed tissue, but also by the mechanical conditions in it (Patel et al., 2010), and the process of precipitation of the polymer is considerably influenced by its molecular mass (Solorio et al., 2010). A system with continuous release of the immunoenhancer thymosin alpha 1 was constructed by dispersion of chitosan or albumin microparticles with this substance in the poly(lactide-co-glycolide) matrices dissolved in N-methyl-2-pyrrolidone. This

The problem of the system Atrigel Technology® is the toxicity of solvents and a sudden initial release of a substantial part of the total dose of the contained active ingredient. In

(Winzenburg et al., 2004), and tissue engineering (Quaglia, 2008).

implant can protect these substances against their enzymatic decomposition.

achieved thymosin release for a period of 15 to 30 days (Liu et al., 2010).

(Savicki & Lunio, 2005).

**6.** *In situ* **forming implants** 

spite of it, in praxis there are antimicrobial and hormonal preparations based on this principle. The system based on the principle of rapid precipitation of the solutions of the biotechnological copolymer PHB/PHC in different solvents was employed to formulate ISFI of the film type acting preventively against adhesions of the tissues as undesirable phenomena in post-surgical applications (Dai et al., 2009).

Other types of ISFI are three-block copolymers of ABA or BAB types based on the gelation of their solutions after administration due to increased temperatures. Oligomers composed of polyethylene glycol blocks and the blocks of polyesters of aliphatic hydroxy acids are advantageous (Quiao et al, 2007; Tang & Singh, 2009). An advantage of the system ReGel® is the absence of toxic organic solvents and a solubilizing potential of the block copolymer. In pharmacotherapeutic praxis the system ReGel® with paclitaxel called OncoGel® is employed (Matthes et al., 2007; ). For some active ingredients, some polymers and some modes of administration a too intensive burst effect, changes in the velocity of release of the active ingredient, or irritability of the polymer, which in the systems is used in higher concentrations, can occur (Packhaeuser et al., 2004).

Instead of polymer solutions in hydrophilic solvents, hydrophobic solvents of lower concentrations than the polymer concentration can be employed. They are thus the plasticized polymers. The behaviour of the system after its administration into the tissue is different, the system is not distributed into the environment. The polymer and possibly the plasticizer are subject to biodegradation, the mechanism of the release of the active ingredient is due to the enzymatic or hydrolytic destruction of the implant. A sufficiently low viscosity can be achieved, besides the use of the plasticizer, by increasing the temperature of the applied system. The maximal painless temperature in humans is stated as 53 °C, the maximal tolerable temperature without necrotic changes is 60 °C (Liu & Wilson, 1998).

The flowable composition relates to a sustained released delivery system with risperidone was patented. It may be injected into the tissue whereupon it coagulates to become the solid or gel, monolitic implant (Dadey, 2010).

An in-situ-hardening paste, containing a biodagradable polymer and water soluble polymeric plasticizer was developed as delivery system for an active agent in the field of tissue regeneration. The hardened paste can be used as bone and cartilage replacement matrix (Hellebrand et. al., 2009).


The following Table 1 presents a survey of hydrophobic plasticizers suitable for ISFI.

Table 1. Characteristics of selected plasticizers with limited miscibility with water.

Pharmaceutical Applications of Plasticized Polymers 79

lactide) and poly(lactide-co-glycolide) were obtained. After preparation using a standard solvent evaporation technique after freeze and oven drying these microparticles contained up to 3 % of water. Residual water markedly decreases Tg values according to Gordon-

The microspheres intended for target oriented drug distribution were prepared from poly(lactic-co-glycolic acid) containing the chemotherapeutic agent etoposide in various concentrations. Plasticization with tricaprin in concentrations of 25 % and 50 % significantly increases the velocity of etoposide release in comparison with the microspheres without a plasticizer (Schaefer & Singh, 2002). The microcapsules containing the active ingredients soluble in water were prepared by the o/o/o emulsion method under the extraction of the solvent. Peanut oil was employed in the middle oily phase of multiple emulsion (Elkharraz et al., 2011). This peanut oil plasticized the internal phase containing a

solution of the active ingredient and poly(DL-lactide) or poly(lactide-co-glycolide) .

The velocity of release of the anticancer agent paclitaxel from poly(lactic-co-glycolic) microspheres was increased after addition of 30 % of isopropyl myristate, 70 % of the active ingredient was released within 3 weeks. After an increase in the concentration of the plasticizer to 50 % there was another increase in the velocity of the process. The plasticizer did not influence the course of degradation of polymers. Release of paclitaxel took place by the mechanism of diffusion from minimatrices (Sato et al., 1996). Analogous conclusions were published in a similar case of microspheres with etoposide (Schaefer & Singh, 2000).

*In situ* forming microparticle systems are based on the emulsification of the solution of the active ingredient and polymer in the outer oily or aqueous phase. After the application of the emulsion there occurs separation of the solvent to the biological environment and solidification of the system. Besides water-soluble solvents it is possible to use the more hydrophobic, in a limited degree water soluble ones, which act as plasticizers. Myotoxicity of the plasticizers of this type is lower; the following series of decreasing toxicity was found: benzylalcohol > triethyl citrate > triacetin > propylene carbonate > ethyl acetate. Myotoxicity of ethyl acetate was comparable with the isotonic sodium

Plasticized polymers play an unsubstitutable role in the formulation of the bioadhesive drug delivery systems (BDDS). Bioadhesive polymers have been formulated into tablets, patches, or microparticles, typically as a matrix into which the drug is dispersed, or as a barrier

In most instances bioadhesive formulations are preferred over the conventional dosage forms, because bioadhesion allows the retention of the active substance in the place of application, or even absorption, and thus increases transmucosal fluxes. As mostly the hepatic first-pass metabolism is avoided, drug bioavailability may be enhanced. Target sites for bioadhesive drug delivery include the eye, GIT, oral cavity, nasal cavity, vagina, and cervix. The development of the adhesive dosage forms for controlled drug delivery to or via mucous membranes is of interest with regard to local drug therapy, as well the systemic administration of peptides and other drugs poorly absorbable from the gastrointestinal

Taylor relationship (Passerini & Craig, 2001).

chloride (Rungseevijitprapa et al., 2008).

**8. Bioadesive plasticized polymers** 

through which the drug diffuses (Ahuja et al., 1997).

ISFI of this type use the protected name Alzamer® Depot technology (Alza Corporation) and are intended for subcutaneous administration. Thanks to the hydrophobic plasticizer, the systems possess a lower speed of degradation with a smaller burst and a slower release of the active ingredient (Matschke et al., 2002). Biocompatibility of plasticizers is higher than in the case of hydrophilic solvents. The advantage of most plasticizers of this type is their low volatility. Proteins and peptides are not dissolved in the systems, their suspensions are chemically very stable (Solanki et al., 2010). For a sufficiently decreased miscibility of ISFI of this type with the surrounding tissue liquid it is necessary to have the solubility of plasticizers in water lower than 7 % (Brodbeck et al., 2000). In situ forming thin membranes were prepared by mixing poly(lactide-co-glycolide) with 10 % polysorbate 80 as the plasticizer (Koocheki et al., 2011).
