Fabrication of Orally Fast-Disintegrating Wafer Tablets Containing Cannabis Extract Using Freeze-Drying Method.

Introduction: The development of a novel dosage form for cannabis extract is necessary to improve drug delivery and also enhance patient convenience. Methods: Orally fast-disintegrating wafer tablets containing cannabis extract, which were prepared using the freeze drying technique, were developed in this work. The formulation consisted of several key components: cannabis extract as the active compound, Tween® 80 as a surfactant and solubilizer, gelatin and mannitol as structural components, sucralose as a sweetening agent, and sodium methylparaben and sodium propylparaben as preservatives. Results: The optimized formulation consists of the following ingredients: 5% cannabis extract, 1.25% Tween® 80, 5% gelatin, 88.34% mannitol, 0.2% sucralose, 0.19% sodium methylparaben, and 0.02% sodium propylparaben. The resulting wafer tablets exhibited the following characteristics: a porous structure, an average weight of approximately 200 mg, minimal weight variation (less than 1.4%), slightly acidic pH (pH 5.12), disintegration within 10 s, low moisture content (less than 3%), a Δ9-tetrahydrocannabinol content of approximately 2.8 mg, and a cannabidiol content of approximately 0.9 mg. Additionally, the wafer tablets rapidly dissolved in simulated saliva fluid containing sodium lauryl sulfate. Conclusion: This work succeeded in the fabrication of orally fast-disintegrating wafer tablets containing cannabis extract with desired properties.

Fabrication of delayed release hard capsule shells from zein/methacrylic acid copolymer blends.

Hard capsule shells with an inherent delayed release action are useful for oral administration of active ingredients, which are acid-labile and/or enzymatically degradable in the gastric environment, without the need of film coating. The objective of this study was to fabricate delayed release hard capsule shells by the dip coating method. The film coating formulations comprised blends of zein and methacrylic acid copolymer (Eudragit® L100-55), with and without the addition of the plasticizer, polyethylene glycol 1000. The rheology parameters (loss modulus (G'), storage modulus (G") and loss tangent (tan δ, G"/G')) of the film coating solution were measured to investigate the processability. Central composite design was used to investigate the main, interaction and quadratic effects of the proportion of methacrylic acid copolymer, solid content of the film formers and level of polyethylene glycol 1000 on the capsule wall thickness and mechanical strength. Multiple response optimization was further conducted, and the design space was established. The in vitro drug release in simulated gastric and intestinal fluids of three different formulations in the design space was compared. The results showed that the tan δ value after the gelation point should be < 0.9 in order to form a thin and sturdy capsule shell. The gelation time and viscosity of the coating solution were related to the thickness of the capsule shell. The study showed that drug release from the capsule with a specified thickness and mechanical strength can be modulated by varying the ratio of zein to methacrylic acid copolymer. The delayed drug release profile was achieved through the capsule shell fabricated from zein to methacrylic acid copolymer at the ratios of 75:25 and 83.2:16.8, with 10% polyethylene glycol 1000.

Effect of cholesterol on the properties of spray-dried lysozyme-loaded liposomal powders.

The influence of cholesterol (Chol) in the liposomal bilayer on the properties of inhalable protein-loaded liposomal powders prepared by spray-drying technique was investigated. Lysozyme (LSZ) was used as a model protein. Feed solution for spray drying was prepared by direct mixing of aqueous solution of LSZ with mannitol solution and empty liposome dispersions composed of hydrogenated phosphatidylcholine and Chol at various molar ratios. The spray-dried powders were characterized with respect to morphology, thermal property, and crystallinity using scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction, respectively. Most formulations gave slightly aggregated, spherical particles, and percentage yields of the spray-dried powders decreased with increasing Chol content. Degree of particle aggregation depended on the powder composition. The powders spontaneously formed liposomes which efficiently entrapped LSZ after reconstitution with HEPES buffered saline (HBS) at 37 degrees C. Lysozyme entrapment efficiency and size distribution of the reconstituted liposomes were evaluated after the powders were reconstituted with HBS. Increasing Chol content resulted in a decrease in size of the reconstituted liposomes and an increase in entrapment efficiency of LSZ. These results correlated with thermal behaviors of the reconstituted liposomes. Biological activity of LSZ was not affected by the spray-drying process. It was also demonstrated that LSZ-loaded liposomal powders could be produced without the need to preload the LSZ into liposomes prior to spray-drying process.

Formulation development of morphine sulfate sustained-release tablets and its bioequivalence study in healthy Thai volunteers.

The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C(max) and AUC(s) were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C(max) and AUC(s) between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC(last) and AUC(inf) between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4-102.6% and 87.7-139.4%, respectively. However, the C(max) of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0-93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one.

Formation of inhalable rifampicin-poly(L-lactide) microparticles by supercritical anti-solvent process.

Formation of inhalable microparticles containing rifampicin and poly(L-lactide) (L-PLA) by using supercritical anti-solvent process (SAS) was investigated. The solutions of drug and polymer in methylene chloride were sprayed into supercritical carbon dioxide. The effect of polymer content and operating conditions, temperature, pressure, carbon dioxide molar fraction, and concentration of solution, on product characteristics were studied. The prepared microparticles were characterized with respect to their morphology, particle size and size distribution, drug content, drug loading efficiency, and drug release characteristic. Discrete, spherical microparticles were obtained at high polymer:drug ratios of 7:3, 8:2, and 9:1. The shape of L-PLA microparticles became more irregular and agglomerated with decreasing polymer content. Microparticles with polymer content higher than 60% exhibited volumetric mean diameter less than 5 microm, but percent drug loading efficiency was relatively low. Drug-loaded microparticles containing 70% and 80% L-PLA showed a sustainable drug release property without initial burst release. Operating temperature level influenced on mean size and size distribution of microparticles. The operating pressure and carbon dioxide molar fraction in the range investigated were unlikely to have an effect on microparticle formation. An increasing concentration of feed solution provided larger size microparticles. Rifampicin-loaded L-PLA microparticles could be produced by SAS in a size range suitable for dry powder inhaler formulation.

Influence of incorporation methods on partitioning behavior of lipophilic drugs into various phases of a parenteral lipid emulsion.

The purpose of this study was to investigate the effect of drug incorporation methods on the partitioning behavior of lipophilic drugs in parenteral lipid emulsions. Four lipophilic benzodiazepines, alprazolam, clonazepam, diazepam, and lorazepam, were used as model drugs. Two methods were used to incorporate drugs into an emulsion: dissolving the compound in the oil phase prior to emulsification (de novo emulsification), and directly adding a concentrated solution of drug in a solubilizer to the emulsion base (extemporaneous addition). Based on the molecular structures and determination of the oil and aqueous solubilities and the partition coefficients of the drugs, the lipophilicity was ranked as diazepam > clonazepam > lorazepam > alprazolam. Ultracentrifugation was used to separate the emulsion into four phases, the oil phase, the phospholipid-rich phase, the aqueous phase and the mesophase, and the drug content in each phase was determined. Partitioning of diazepam, which has the highest lipophilicity and oil solubility among the four drugs, was unaffected by the drug incorporation method, with both methods giving a high proportion of drug in the inner oil phase and the phospholipid-rich phase, compared to the aqueous phase and mesophase. Partitioning of the less lipophilic drugs (alprazolam, clonazepam, and lorazepam) in the phases of the emulsion system was dependent on the method of incorporation and the drug solubility properties. Emulsions of the three drugs prepared by de novo emulsification exhibited higher drug localization in the phospholipid-rich phase compared to those made by extemporaneous addition. With the latter method, the drugs tended to localize in the outer aqueous phase and mesophase, with less deposition in the phospholipid-rich phase and no partitioning into the inner oil phase.

The influence of physicochemical properties of preservative compounds on their distribution into various phases of oil in water submicron emulsion.

Phospholipids--stabilized submicron emulsions require the addition of preservatives to destroy or inhibit the growth of microorganisms when these preparations are non-sterile products or when packed in multi-dose containers. This study examined the distribution of four paraben esters--methylparaben, ethylparaben, propylparaben, and butylparaben--that were added into submicron emulsions by de novo emulsification. The distribution of preservative compounds among different phases was determined after separation of submicron emulsions by ultracentrifugation. The compounds with higher lipophilicity were concentrated in the oil phase and phospholipids-rich phase, leading to an increase in oil droplet size. However, the effect of the paraben distribution on zeta potential and pH of emulsion fluctuated depending on the type of phospholipid used. The lower lipophilic compounds were mostly found in the aqueous phase and mesophase. These results signify the possibility that the chemical structures and lipophilicity of preservative compounds affected their distribution in phospholipid-stabilized submicron emulsions. We conclude that the higher concentration of preservatives or their combination may be required for efficient preservation of submicron emulsion products.

Spherical composite particles of rice starch and microcrystalline cellulose: a new coprocessed excipient for direct compression.

Composite particles of rice starch (RS) and microcrystalline cellulose were fabricated by spray-drying technique to be used as a directly compressible excipient. Two size fractions of microcrystalline cellulose, sieved (MCS) and jet milled (MCJ), having volumetric mean diameter (D50) of 13.61 and 40.51 microm, respectively, were used to form composite particles with RS in various mixing ratios. The composite particles produced were evaluated for their powder and compression properties. Although an increase in the microcrystalline cellulose proportion imparted greater compressibility of the composite particles, the shape of the particles was typically less spherical with rougher surface resulting in a decrease in the degree of flowability. Compressibility of composite particles made from different size fractions of microcrystalline cellulose was not different; however, using MCJ, which had a particle size range close to the size of RS (D50 = 13.57 microm), provided more spherical particles than using MCS. Spherical composite particles between RS and MCJ in the ratio of 7:3 (RS-MCJ-73) were then evaluated for powder properties and compressibility in comparison with some marketed directly compressible diluents. Compressibility of RS-MCJ-73 was greater than commercial spray-dried RS (Eratab), coprocessed lactose and microcrystalline cellulose (Cellactose), and agglomerated lactose (Tablettose), but, as expected, lower than microcrystalline cellulose (Vivapur 101). Flowability index of RS-MCJ-73 appeared to be slightly lower than Eratab but higher than Vivapur 101, Cellactose, and Tablettose. Tablets of RS-MCJ-73 exhibited low friability and good self-disintegrating property. It was concluded that these developed composite particles could be introduced as a new coprocessed direct compression excipient.

Preparation and in vivo absorption evaluation of spray dried powders containing salmon calcitonin loaded chitosan nanoparticles for pulmonary delivery.

PURPOSE: The aim of the present study was to prepare inhalable co-spray dried powders of salmon calcitonin loaded chitosan nanoparticles (sCT-CS-NPs) with mannitol and investigate pulmonary absorption in rats. METHODS: The sCT-CS-NPs were prepared by the ionic gelation method using sodium tripolyphosphate (TPP) as a cross-linking polyion. Inhalable dry powders were obtained by co-spray drying aqueous dispersion of sCT-CS-NPs and mannitol. sCT-CS-NPs co-spray dried powders were characterized with respect to morphology, particle size, powder density, aerodynamic diameter, protein integrity, in vitro release of sCT, and aerosolization. The plasmatic sCT levels following intratracheal administration of sCT-CS-NPs spray dried powders to the rats was also determined. RESULTS: sCT-CS-NPs were able to be incorporated into mannitol forming inhalable microparticles by the spray drying process. The sCT-CS-NPs/mannitol ratios and spray drying process affected the properties of the microparticles obtained. The conformation of the secondary structures of sCTs was affected by both mannitol content and spray dry inlet temperature. The sCT-CS-NPs were recovered after reconstitution of spray dried powders in an aqueous medium. The sCT release profile from spray dried powders was similar to that from sCT-CS-NPs. In vitro inhalation parameters measured by the Andersen cascade impactor indicated sCT-CS-NPs spray dried powders having promising aerodynamic properties for deposition in the deep lung. Determination of the plasmatic sCT levels following intratracheal administration to rats revealed that the inhalable sCT-CS NPs spray dried powders provided higher protein absorption compared to native sCT powders. CONCLUSION: The sCT-CS-NPs with mannitol based spray dried powders were prepared to have appropriate aerodynamic properties for pulmonary delivery. The developed system was able to deliver sCT via a pulmonary route into the systemic circulation.

Slow release formulations of inhaled rifampin.

Rifampin microspheres were prepared by spray drying using either polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) polymers in different drug to polymer ratios (90:10 to 5:95, w/w). The in-vitro release characteristics, particle-size distribution, and cytotoxicity (in an alveolar macrophage cell line) and pharmacokinetics in rats after pulmonary instillation were evaluated. Increasing the polymer content from 10% to 95% slowed down the in vitro drug release with PLGA particles showing a steeper change with increasing polymer content (100% to 20% drug release over 6 h) than PLA particles (88% to 42% drug release over 6 h). PLA microsphere formulations revealed lack of cytotoxicity and a mass median aerodynamic diameter (MMDA) of 2.22-2.86 mum, while PLGA particles were larger (MMDA of 4.67-5.11 mum). Pharmacokinetics differed among the formulations with the 10% PLA formulation showing a distinct sustained release (t (max) of 2 h vs 0.5 h of free drug) and a systemic bioavailability similar to that of free drug. Formulations with high polymer content showed a lower relative bioavailability (30%). This suggested that an optimal release rate existed for which a distinct amount of drug was delivered over an extended period of time.

Miscibility and interactions between 17beta-estradiol and Eudragit RS in solid dispersion.

Miscibility of 17beta-estradiol and Eudragit RS in solid dispersions was determined by modulated temperature differential scanning calorimetry (MTDSC). A reduction of the 17beta-estradiol melting point in Eudragit RS solid dispersions was observed by MTDSC using heating program I in which the maximum temperature in the first heating run was lower than the 17beta-estradiol melting point. The melting point depression of 17beta-estradiol in solid dispersions as a function of composition could be explained by the Nishi-Wang equation indicating an interaction between 17beta-estradiol and Eudragit RS in the system. A variation of glass transition temperature (T(g)) of 17beta-estradiol in Eudragit RS solid dispersion was observed by MTDSC using heating program II in which the maximum temperature in the first heating run reached the 17beta-estradiol melting point. In the second heating run of heating program II, 17beta-estradiol was in an amorphous form blended with Eudragit RS. The variation in T(g) of amorphous 17beta-estradiol blended with Eudragit RS could be explained by the Kwei equation, a modified version of the Gordon-Taylor equation. The parameter estimates from the Kwei equation were consistent with an interaction between 17beta-estradiol and Eudragit RS, which was due to inter-associated hydrogen bonding as deduced from the FTIR spectra of the blends.

Preparation and in vitro release of dual-drug resinates containing equivalent content dextromethorphan and diphenhydramine.

The dual-drug resinate containing equivalent content of dextromethorphan hydrobromide (DTM) and diphenhydramine hydrochloride (DPH) was developed and characterized. To achieve this specific resinate, a procedure of simultaneous dual-drug loading using loading solutions composed of different proportions of DTM and DPH was performed and a dual-drug loading diagram was constructed to determine the equivalent drug loading solution (ELS) and also the estimated equivalent drug content (EQC). The effects of resin crosslinkage, overall drug concentration of the loading solution, and temperature during drug loading on the values of ELS and EQC were assessed. The increased overall drug concentration from 0.25 to 1.0% w/v elevated the EQC values from 18 to 35% w/w for low crosslinked resins (Dowex 50 W x 2 and x 4), and from 18 to 27% w/w for high crosslinked resin (Dowex 50 W x 8). It also changed the values of ELS from 0.50 to 0.48 for the low crosslinked resins, and 0.50 to 0.55 for the high crosslinked resin. For the high crosslinked resin, the applied heat from 35 to 65 degrees C further increased the values of EQC from 27 to 32% w/w, and changed the values of ELS in the reverse direction from 0.55 to 0.48. However, the heat did not exert significant effects on the values of EQC and ELS for the low crosslinked resins. Different batches of dual-drug resinates prepared from the determined ELS provided the resultant resinates with equivalent contents of DTM and DPH which were very close to the estimated EQC. The drug release from the resinates was performed in 0.05, 0.1, 0.2, and 0.4 N of KCl solutions. The increased ionic strength generally accelerated the release of both drugs except for 0.4 N KCl solution in which the drug release from the resinates of high crosslinkage was decreased. The congestion on the outward movement of drugs through the high crosslinked matrix might cause the delay of drug release. In conclusion, the release study demonstrated that the dual-drug resinate using a suitable crosslinked resin could be used for extended delivery of two combined drugs with the equivalent therapeutic dose.

Release characteristics of the matrices prepared from co-spray-dried powders of theophylline and ethylcellulose.

Co-spray-dried powders of theophylline and ethylcellulose were prepared using aqueous ethylcellulose dispersion. Co-spray-dried powders were directly compressed into the matrices and the release characteristics of the prepared matrices were investigated. The co-spray-dried powders exhibited good matrix formations with high hardness at rather low compression force. The concentration of ethylcellulose in the matrices was, as expected, the rate-determining factor in controlling the release rate of the drug. Increasing the weight fractions of ethylcellulose resulted in a corresponding decrease in the drug release rates in both 0.1 N HCl and phosphate buffer pH 6.8. However, at the same level of ethylcellulose content, the drug release in acidic conditions was higher than in alkaline medium. To modify release characteristics of the matrices, PVP K30 and lactose were employed as channeling agents. At concentrations of 5 and 10%, PVP K30 was found to slow the drug release when incorporated into the co-spray-dried powder formulations containing 5% ethylcellulose. Lactose at a concentration of 15% provided an increasing effect on drug release when added in the formulations. But an increase in lactose quantity from 15 to 25% did not exert much more influence on release characteristics. Higuchi plots were found to be best applicable to all release data. Scanning electron microscopic examinations on the surface and cross-section of the matrices before and after subjection to release testing revealed the formation of porous networks within the matrices by the ethylcellulose fibers. Such polymeric networks would account for the controlled diffusion of the drug from the matrices.