Studies On The Construction And Evaluation Of Carbamazepine Modified Release System

Oral route of administration is the most convenient, common and preferred for clinical therapy and a lot of drugs has been prepared as oral dosage form. However, approximately70%of new drug candiates being developed by the pharmaceutical industry in recent years are poorly water soluble. Currently, almost40%of immediate release drugs in the market are practically insoluble. Their oral bioavailability is affected by a variety of factors which influence their absorption from the gastrointestinal tract. Of particular interest is the poorly water soluble, highly permeable active pharmaceutical ingredients (APIs) which categorized into the biopharmaceutics classification system (BCS) class Ⅱ. For instance, cyclosporine, griseofulvin, and itraconazole are defined as this class. Generally, the limiting factor to the in vivo absorption of BCS Class Ⅱ drugs after oral administration is their inadequate dissolution rates. Therefore, an enhancement of the dissolution rate is thought to be a key determinant for improving the oral bioavailability of BCS class Ⅱ drugs.CBZ,5H-Dibenz[b,f]azepine-5-carboxamide, is a model drug belonged to BCS class Ⅱ with an experimental logP value of2.45and practically insoluble in water (120μg/ml). It is widely used as an anticonvulsant drug and in the therapy of trigeminal neuralgia for40years. CBZ is commonly administered orally as a solid, however, due to the limited dissolution rate, its absorption is slow, erratic and unpredictable in humans, leading to incomplete bioavailability and considerable variability in plasma concentration. Furthermore, CBZ exhibits at least four polymorphic forms and variations dissolution and absorption also occurred between them. However, with a narrow therapeutic index, a high dose of CBZ is also required. It is important to improve the dissolution rate of CBZ and thus increase its degree and rate of absorption, and hence its oral bioavailability. This can reduce the necessary dosage and frequency of dosing and probably reduce its side effects. Many different approaches have been applied to increase the bioavailability of CBZ, such as complexation with substituted cyclodextrins, solid dispersion, nanoemulsions or microemulsions, microspheres, conversion to amorphous form and so on. The use of amorphous solid form is arousing more and more interests and attentions in recent years.Amorphous form is a special physical state of solid compounds that the positions of the molecules or atoms have no long-range order. Sometimes amorphous compounds have better bioavailability, or achieve ultra-fast absorption in situation of acute and intermittent symptoms than that of morphous compounds, thus change drug efficacy. It has higher molecular mobility, free energy and more entropic compared to the corresponding crystalline state with the long range order. The common techniques for producing an amorphous form are mechanical activation, solution-or melt-mediated transformations of bulk material, such as milling, quench cooling of a drug melt, melt extrusion, spray drying, freeze drying. However, due to the higher energetic state, the amorphous form is kinetically and thermodynamically unstable and has the tendency to convert to a more stable, less energetic crystal form(at least if it is a small molecular weight organic). Storage conditions (time, temperature and humidity) have been identified as main factors influencing the rate of recrystallisation. Upon most occasions, in order to enhance the physical stability of the amorphous drugs and dosage forms, the drug is always combined with a polymer by decreasing the free volume, consequently increasing the glass transition temperature (Tg) and slowing down the crystallization process with the disruption of drug-drug interactions. Sometimes, the stability of the same amorphous systems using different preparation techniques may be different in the drug delivery. Therefore, it is a great challenge to obtain the amorphous formulation with a certain degree of solid solubility, miscibility and kinetic stabilization.Thin film freezing (TFF) particle engineering process to produce pharmaceutical powders is an evolution of earlier freezing processes on cold surfaces to form films. Impingement and solidification of liquefied droplets onto a cold solid surface has been used in the electrical and semi-conductor industries to add thin layers of frozen material onto a surface. Only recently has this application been used as a particle engineering technique to improve the bioavailability of poorly water soluble compounds and biopharmaceuticals. TFF involves applying a API/stabilizers solution onto a cryogenically-cooled solid surface to obtain a solid dispersion/solution, collecting the frozen particles and removing the solvent via lyophilization. Nanostructrued powders with high surface area, increased wettability, amorphous API structure and rapid dissolution rates were obtained successfully.The major objectives of undertaking this study were to prepare amorphous powder of CBZ by TFF, incorporate TFF carbamazepine formulations(CBZ-TFF) into capsule dosage form for modified release, establish the CBZ determine method by HPLC-UV for in vitro and in vivo samples analysis, study the bioavailability of CBZ-TFF and to evaluate the potential of using TFF as oral amorphous powder engineering process for poorly water soluble drugs.The major contents include preformulation study, technology and formulation screening of preparation carbamazepine modified release amorphous powders by TFF and then encapsuled into capsules, establishment of HPLC-UV method for biological specimen analysis, single-dose24-h pharmacokinetic studies of Sprague-Dawley(SD) rats oral administration of the three kinds of preparations by rat capsule dosing apparatus.The established HPLC-UV method for in vitro sample, analysis was investigated and corresponded to technology requirement. The experiment results of preformulation study stated that the equilibrium solubility of CBZ is with small difference under the condition of gastrointestinal pH value. The oil/water partition coefficient of carbamazepine was less influence by pH and the lgP is between1.0to1.5which indicate that CBZ should be easily absorbed by epithelial cells in gastrointestinal tract, which also hinted that the poor oral bioavailability of carbarmazepine was mainly due to the low solubility resulted slow dissolution vdocity.The formula and preparation of CBZ modified release drug delivery were investigated:(1) polymer type;(2) drug:polymer ratio. The physical mixtures were mixed by geometric dilution and trituration using a ceramic mortar and pestle with CBZ and different kinds of polymers:(1) immediate release polymers, including Polyvinylpyrrolidone K30(PVP K30) and premium hydroxypropyl methylcellulose (HPMC E3);(2) enteric polymers, including hydroxypropyl methyl-cellulose phthalate NF (HP-55), Eudragit(?) L100-55(L100-55) and hydroxypropyl methylcellulose acetate succinate (HPMCAS AS-MF);(3) controlled release polymers, including Eudragit(?) RS-PO (RS-PO) and Cellulose Acetate (CA). The ratio of the drug and each polymer has seven levels:1:4;1:3;1:2;1:1;2:1;3:1;4:1. Differential scanning calorimetry (DSC) was utilized to define the level of CBZ miscibility with each polymer and the glass transition temperature (Tg) was selected as the response variable to optimize the CBZ-TFF formulations. DSC profiles revealed that completely miscible at every level of ratio with drug and each polymer. However, Tg of physical mixtures decreased with increasing CBZ potency, especially for HPMCAS AS-MF and Eudragit(?) RS-PO. The Tg of physical mixtures with HP-55and HPMCAS AS-MF as polymers were always at low level. There is small contribution for improving the Tg of the drug, which maybe cause the instability of the drug systems.Studies of CBZ nanostructured aggregate powder for modified release1. Development and evaluation of CBZ nanostructured aggregate powder for immediate releaseImmediate release nanostructured aggregate powder containing amorphous CBZ and immediate release polymers were successfully manufactured using TFF process. The MDSC was used to define the miscibility of CBZ and each polymer. The compositions were completely miscible with1:2CBZ:polymer ratio for two polymers, however, recrystallization exotherms were observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added immediate release polymer with1:1CBZ:polymer ratio at least. The TFF power samples presented as highly regular porous matrix structure under SEM. Dissolution studies on CBZ-HPMC E3(1:1) and CBZ-PVP K30(2:1) compositions were performed under sink conditions in0.1N HCl for2h and then pH6.8phosphate buffer for6h. At lease85%CBZ quickly dissolved within2h, which is a function of the hydrophilic polymers.2. Development and evaluation of CBZ nanostructured aggregate powder for delayed releaseDelayed release micronized powers containing amorphous CBZ and enteric polymers were also successfully manufactured using TFF process. The compositions were completely miscible with2:1CBZ:polymer ratio for three polymers and as high as4:1in HPMCAS AS-MF, however, recrystallization exotherms were also observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added enteric polymer with3:1CBZ:polymer ratio at least. A highly porous structure with more regularly shaped particles of the CBZ-TFF powder was observed under SEM. Furthermore, the wettability of formulations with various polymer types exhibited similar and significantly enhanced. Dissolution rates on CBZ-HPMCAS AS-MF (1:2), CBZ-L100-55(1:2) and CBZ-HP-55(1:2) compositions were studied under sink conditon. At lease40%CBZ dissolved in2h, and changed for the phosphate buffer, samples revealed rapid dissolution with at least80%CBZ dissolved within15min, which maybe caused by the dynamic dissolving characteristic of the enteric polymer.3. Development and evaluation of CBZ nanostructured aggregate powder for controlled releaseControlled release micronized powers containing amorphous CBZ and controlled release polymers were also successfully manufactured using TFF process. The compositions were completely miscible with1:1CBZ:polymer ratio for two polymers, however, recrystallization exotherms were also observed in some formulations which revealed phase separation occurred during power formation. XRD results indicated that carbamazepine was amorphous for each added polymer with1:1CBZ:polymer ratio at least. A highly porous structure with more regularly shaped particles of the CBZ-TFF powder was observed under SEM. Furthermore, the wettability of formulations with various polymer types exhibited similar and slightly enhanced. Dissolution rates on CBZ-RS-PO (1:2) and CBZ-CA (2:1) compositions were studied under sink conditon. The behavior of the CBZ release in the dissolution medium was less influenced by the pH and samples revealed controlled released dissolution within8h, which maybe because of the insolubility of the controlled released polymers.The amorphous CBZ-TFF powders for modified release were stored in desiccators under vacuum at room temperature, and the physical stability was assessed by XRD at1,3and6months. There were no characteristic crystalline peak of CBZ detected with the formulations of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA after storage for up to6months, indicating the powders retained amorphous morphology when stored at room temperature and protected from humidity.The modified release capsules of the CBZ-TFF were prepared by dry granulation tabletting and grinding method using Silicified Microcrystalline Cellulose (SMCC), Magnesium stearate (Mgst) and Sodium Starch Glycolate (SSG) as supporting agents in order to obtain better physical and chemical stabilities. The stability of modified release capsules of the CBZ-TFF were not affected by the preparation procedures with nearly unchanged main quality indexes. The release trail in vitro were investigated and the results showed that the CBZ-TFF nanostructured aggregate powders and CBZ-TFF modified release capsules have similar release kinetic. The three preparations had immediate release, delayed release and controlled release characters, respectively.Carbamazepine and its major active metabolite carbamazepine-10,11-epoxide (CBZ-E) were determined in the blood plasma by HPLC. The technology investigation coincided with the requirement of SFDA guidance principle of chemicals non-clinic pharrnacokinetics. Pharmacokinetic parameters were derived using a non-compartmental model PK Solver2.0in Microsoft Excel. For carbamzepine, after oral administration (30mg-Kg-1), three kind of modified release delivery systems showed approximately2.4times,2.6times and2.5times bioavailability improvements in terms rate and extent compared with the crude CBZ. The crude CBZ has the longest MRT, the CBZ-CA showed shorter and the CBZ-HPMC E3showed the shortest. The tmax was significantly longer for the crude CBZ than that for the capsules of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. For CBZ-E, after oral administration (30mg·Kg-1), three kind of modified release delivery systems showed approximately2.6times,3.2times and3.0times bioavailability improvements in terms rate and extent compared with the crude CBZ. The crude CBZ has the longest MRT, the CBZ-CA showed shorter and the CBZ-HPMC E3showed the shortest. The tmax was significantly longer for the crude CBZ than that for the capsules of CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. Based on comparison of the AUCO-co values of carbamazepine and CBZ-E, the crude CBZ showed significantly lower carbamazepine exposure than the delivery systems (CBZ-HPMC E3, CBZ-L100-55and CBZ-CA). There was no significant difference in AUCo-oo among CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. The Cmax of carbamazepine and CBZ-E were significantly lower in the crude carbamazepine than those of the capsules CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. In contrast to the crude CBZ, the CBZ-TFF formulations had shorten t1/2and augmented AUC. No adverse events were observed during the administration. The AUC of the crude CBZ was lower than that of the modified release capsules, including CBZ-HPMC E3, CBZ-L100-55and CBZ-CA. Although the solution has longer MRT the lower Cmax as well as other parameters also lead to a distinct pharmacokinetics profile when compared to the modified release capsules plots. Therefore, these experiments demonstrated that nanostructured aggregate powder prepared by TFF can be used to improve exposure of compounds with low dissolution rate and poor phatmacokinetic characteristics.In conclusion, we have successfully incorporated carbamazepine, a poorly soluble drug, into modified release systems by a thin film freezing(TFF) process. Three kinds of modified release micronized powders containing amorphous CBZ and polymers-including HPMC E3, L100-55, CA, were successfully prepared and then encapsuled into capsules. The systems ware physically stable for3months at room temperature and the drug dissolution rates from three kinds of capsule preparations were significantly modified and enhanced compared to the crude drug. The amorphous state of the drug and the modified dissolution rate contributed to a significantly enhanced oral bioavailability compared to the crude CBZ. These data collective support that nanostructured aggregate powder prepared by TFF is a promising delivery system to enhance the oral absorption of poorly water soluble drugs.