New Biodegradable Poly(l-lactide)-Block-Poly(propylene adipate) Copolymer Microparticles for Long-Acting Injectables of Naltrexone Drug

Abstract

In the present study, novel block copolymers of poly(l-lactide)-block-poly(propylene adipate) (PLLA-b-PPAd) were synthesized in two ratios, 90/10 and 75/25 w/w and were further investigated as long-acting injectable (LAI) polymeric matrices in naltrexone base microparticle formulations. The synthesized polymers were characterized by 1 H-NMR, 13 C-NMR, FTIR, XRD, TGA and DSC. NMR and FTIR spectroscopies confirmed the successful synthesis of copolymers while DSC showed that these are block copolymers with well-defined and separated blocks. Microparticles were prepared by single emulsification method and were further characterized. Nanoparticles in the range of 0.4-4.5 µm were prepared as indicated by SEM, with copolymers giving the lowest particle size. By XRD and DSC it was found that naltrexone was present in the amorphous state in its microparticles. Dissolution study showed a drug release extending over seven days, indicating that these novel PLLA-b-PPAd copolymers could be promising matrices for naltrexone's LAI formulations. It was evidenced that drug release depended on the copolymer composition. Model release studies showed that drug release is controlled by diffusion.Polymers 2020, 12, 852 2 of 24 as drug carriers are ε-polycaprolactone (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), their copolymer poly(lactide-co-glycolide) (PLGA), which are typically prepared by ring-opening polymerizations, and polyesters resulting from the polycondensation of an aliphatic diol and an aliphatic dicarboxylic acid such as poly(ethylene succinate), poly(ethylene adipate), poly(propylene adipate) (PPAd). Among them, PLA is by far the most extensively studied. However, the use of PLA suffers from some limitations due to its high crystallinity and low hydrolysis rate. Copolymerization is an easy method to modulate the properties of a polymer, by varying the rigidity/flexibility of polymer chains, the hydrophilic/hydrophobic balance and the amorphous/crystalline ratio [3]. Copolymerization of PLA with more hydrophilic and amorphous polymers has been carried out to modify the required biomaterial properties for specific applications [4].Naltrexone base (NTX) is a specific opioid antagonist, used in the treatment of both drug addiction and alcohol dependence. It is marketed in tablet form for oral administration but has some pharmacotherapeutic limitations (for example, a low oral bioavailability, as 98% of the drug is metabolized in the liver) and gastrointestinal side effects (nausea, abdominal pain, and vomiting). Treatment by oral administration of NTX requires a daily administration and its efficacy can be compromised due to the patient's non-compliance. Indeed, 37% of patients discontinue the daily oral use of NTX by 12 weeks and more than 80% discontinue its use by six months [5]. Currently there are two major types of sustained-release formulations for NTX delivery: (a) injectable depot formulations for long-acting release (Naltrel ® , Vivitrol ® , and Depotrex ® ), and (b) surgically implantable pellets (Pro...

Synthesis of Dacus Pheromone, 1,7-Dioxaspiro[5.5]Undecane and Its Encapsulation in PLLA Microspheres for Their Potential Use as Controlled Release Devices

“…As the amount XRD was used in order to determine the crystallinity of PLLA microparticles before and after DSU's encapsulation. PLLA is a semicrystalline polymer, as has been previously reported [19] and its recorded pattern is shown in Figure 4. Two characteristic peaks of PLLA at 16.6 and 18.8 deg were present, while after DSU encapsulation there was a reduction to intensity of the peaks.…”

“…Polymeric microspheres containing 1,7-dioxaspiro [5.5]undecane were prepared by oil-water (o/w) emulsification method, as was previously reported by Nanaki et al [16,19,25]. In brief, PLLA was dissolved in 5 mL dichloromethane and 1,7-dioxaspiro [5.5]undecane was inserted in the polymeric solution in ratios 5, 10 and 20% w/w followed by probe sonicator for 1 min, cycle 1, amplitude 100% (UP50H, Hielscher Ultrasound Technology, Teltow, Germany).…”

“…Microparticles were prepared according to o/w technique as described previously [16,18,19]. SEM ( Figure 2) was used in order to verify microparticles formation as well as their surface morphology.…”

“…It can be derived from natural and renewable resources such as potato, corn, cane molasses and beet sugar, while its bioabsorbable character and its promising mechanical properties surely make it an attractive and useful biodegradable polymer with a wide range of applications [15]. PLA is mainly used in biomedical application and drug delivery systems [16][17][18][19] in the form of micro-and nanoparticles [20,21]. The advantage of these systems is that the active compound is homogeneously encapsulated in PLA particles and the release of them can last for many days.…”

Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Amphiphilic Copolymers for Long-Acting Injectables: Synthesis, Non-Acylating Performance and In Vivo Degradation

“…Long acting injectables (LAIs) have achieved wide success due to their numerous clinical benefits over oral therapies, such as enhanced adherence to treatment, increased bioavailability for some drugs and avoidance of first-pass metabolism [ 1 , 2 , 3 , 4 , 5 ]. For these reasons, in the last decades this therapeutic route has become increasingly ubiquitous in the cure of chronic health conditions and long-term illnesses [ 6 , 7 , 8 ]. Additionally, differently from traditional non-degradable releasing implants, bioresorbable LAIs do not require surgical removal once the medical treatment is completed.…”