Spray freeze-dried porous microparticles of a poorly water-soluble drug for respiratory delivery.

Particles of poorly water-soluble drugs were prepared to develop a dry powder inhaler (DPI). Spray freeze-drying (SFD) technique using a four-fluid nozzle (4N), which has been developed by authors, was applied in this research. Ciclosporin and mannitol were used as a poorly water-soluble model drug and a dissolution-enhanced carrier, respectively. The organic solution of ciclosporin and aqueous solution of mannitol were separately and simultaneously atomized through the 4N, and the two solutions were collided with each other at the tip of the nozzle edge. The spray mists were immediately frozen in liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier. tert-Butyl alcohol (t-BuOH) was used as the organic spray solvent due to its relatively high freezing point. The resultant composite particles with varying drug content were characterized depending on their morphological and physicochemical properties. The particles contained amorphous ciclosporin and δ-crystalline mannitol. The characteristic porous structure of SFD particles potentially contributed to their good aerodynamic performance. A series of particles with a similar size distribution and different drug content revealed that the incorporation of mannitol successfully improved the cohesive behavior of ciclosporin, leading to enhanced aerosol dispersion. The dissolution test method using low-volume medium was newly established to simulate the release process from particles deposited on the surface of the bronchus and pulmonary mucosa. The composite with hydrophilic mannitol dramatically improved the in vitro dissolution behavior of ciclosporin in combination with the porous structure of SFD particles.

Evaluation of disintegration properties of orally rapidly disintegrating tablets using a novel disintegration tester.

This report describes a new disintegration tester that can determine not only the disintegration time of orally rapidly disintegrating tablets (ODT), but also the disintegration behavior and mechanism. Using the tester, the disintegration properties of the tablets prepared in a previous study were examined. The purpose of this study is to confirm the utility of the tester as an instrument for evaluating the disintegration properties of ODT and determine relations among time, behavior and mechanism of the disintegration. Results demonstrated that in vitro disintegration time in the tester is similar to that in the commercial disintegration tester for ODT and is highly correlated with oral disintegration time. Observations of disintegration process revealed that a difference in disintegration behavior between tablets compressed at 50-75 MPa and 100 MPa; the disintegration behavior of the tablets were designated immediate disintegrating type and gradual disintegrating type, respectively. The dynamic swelling profile and water absorption profile indicated that the disintegration mechanism of the tablets involved wicking action induced by swelling of the disintegrant; the disintegration time was closely related to the initial rates of swelling and water absorption. Furthermore, the mechanism of water absorption of tablets compressed at 50-75 MPa and 100 MPa shows anomalous diffusion and case-II transport, respectively. The shift in this mechanism is consistent with differences in disintegration time and behavior between the tablets. These findings suggest that information on disintegration properties obtained by our tester is useful for understanding of disintegration phenomena of ODT.

Novel ultra-cryo milling and co-grinding technique in liquid nitrogen to produce dissolution-enhanced nanoparticles for poorly water-soluble drugs.

A novel ultra-cryo milling micronization technique for pharmaceutical powders using liquid nitrogen (LN2 milling) was used to grind phenytoin, a poorly water-soluble drug, to improve its dissolution rate. LN2 milling produced particles that were much finer and more uniform in size and shape than particles produced by jet milling. However, the dissolution rate of LN2-milled phenytoin was the same as that of unground phenytoin due to agglomeration of the submicron particles. To overcome this, phenytoin was co-ground with polyvinylpyrrolidone (PVP). The dissolution rate of co-ground phenytoin was much higher than that of original phenytoin, single-ground phenytoin, a physical mixture of phenytoin and PVP, or jet-milled phenytoin. X-Ray diffraction showed that the crystalline state of mixtures co-ground by LN2 milling remained unchanged. The equivalent improvement in dissolution, whether phenytoin was co-ground or separately ground and then mixed with PVP, suggested that even when co-ground, the grinding of PVP and phenytoin occurs essentially independently. Mixing original PVP with ground phenytoin provided a slight improvement in dissolution, indicating that the particle size of PVP is important for improving dissolution. When mixed with ground phenytoin, PVP ground by LN2 milling aided the wettability and dispersion of phenytoin, enhancing utilization of the large surface area of ground phenytoin. Co-grinding phenytoin with other excipients such as Eudragit L100, hypromellose, hypromellose acetate-succinate, microcrystalline cellulose, hydroxypropylcellulose and carboxymethyl cellulose also improved the dissolution profile, indicating an ultra-cryo milling and co-grinding technique in liquid nitrogen has a broad applicability of the dissolution enhancement of phenytoin.

Development of formulation device for periodontal disease.

In addition to providing standard surgical treatment that removes the plaque and infected tissues, medications that can regenerate periodontal tissue are also required in the treatment of periodontal disease. As a form of regenerative medication, various growth factors are expected to be used while treating periodontal disease. A protein-like growth factor is often developed as a lyophilized product with dissolution liquid, considering its instability in the solution state. We have clarified that the formulation for periodontal disease needs to be viscous. When the lyophilized product was dissolved using a sticky solution, various problems were encountered, difficulty in dissolving and air bubbles, for example, and some efforts were needed to prepare the formulation. In this research, to identify the problem of preparing a viscous formulation, a lyophilized product (placebo) and sticky liquid were prepared by using vial and ampoule as the conventional containers. Based on these problems, a prototype administration device was developed, and its functionality was confirmed. As a result, it was suggested that the device with a useful mixing system that could shorten the preparation time was developed.

Design of dry nanosuspension with highly spontaneous dispersible characteristics to develop solubilized formulation for poorly water-soluble drugs.

PURPOSE: The powderization of the aqueous nanosuspension of a poorly water-soluble drug, which was prepared by wet-milling technique developed by authors, was investigated to apply to the development of solid dosage forms. METHODS: Drug particles were suspended and milled in the aqueous medium using the oscillating beads-milling apparatus. The recovered nanosuspension was spray-dried 1) with no additive or 2) with co-dissolving mannitol as a nanoparticle carrier. As a control, the solution of the drug and additives with the same formulation as nanosuspension was also spray-dried. RESULTS: SEM observation and X-ray powder diffraction analysis revealed that the dried products from suspension formed a spherical particle with single-micron diameter, which was composed of thousands of nano-sized crystalline drug fragment. It was also found that the dried products from suspension could be spontaneously redispersed in water, transforming into nanosuspension with the original size distribution. Such dried powder with high dispersibility was named "dry nanosuspension." The dry nanosuspension had immediate release behaviors in gastrointestinal buffered media, whereas the dried product from solution showed the poor dispersion and dissolution properties even if same content of additives were loaded. CONCLUSIONS: The present technique with combination of wet nano-milling and spray-drying processes would be a novel approach to develop the pharmaceutical products with poorly water-soluble and oral-absorbable drugs.

Preparation and evaluation of orally rapidly disintegrating tablets containing taste-masked particles using one-step dry-coated tablets technology.

In this study, in order to address the problems with manufacturing orally rapidly disintegrating tablets (ODT) containing functional (taste masking or controlled release) coated particles, such as the low compactability of coated particles and the rupture of coated membrane during compression, a novel ODT containing taste-masked coated particles (TMP) in the center of the tablets were prepared using one-step dry-coated tablets (OSDrC) technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method, and the properties of the tablets and the effect of compression on the characteristics of TMP were evaluated. OSDrC was found to have higher tensile strength and far lower friability than PM, but the oral disintegration time of OSDrC is slightly longer than that of PM following high compression pressure. Consequently, OSDrC approaches the target tablet properties of ODT, whereas PM does not. The deformation of TMP in OSDrC due to compression is slight, and the release rate of acetaminophen (AAP) from OSDrC is the same as from TMP. However, TMP on the surface of PM are considerably deformed, and the release rate of AAP from PM is faster than from TMP. These findings suggest that OSDrC technology is a useful approach for preparing ODT containing functional coated particles. Furthermore, we demonstrate that the elastic recovery of tablets can affect differences in the properties of OSDrC, PM and placebo tablets (PC).

Novel spray freeze-drying technique using four-fluid nozzle-development of organic solvent system to expand its application to poorly water soluble drugs.

Spray freeze-drying (SFD) technique using four-fluid nozzle (4N), which is a novel particle design technique previously developed by authors, has been further developed to expand its application in pharmaceutical industry. The organic solvent was utilized as a spray solvent to dissolve the poorly soluble drug instead of conventional aqueous solution. Acetonitrile solution of the drug and aqueous solution of the polymeric carrier were separately and simultaneously atomized through 4N, and collided each other at the tip of nozzle edge. The spray mists were immediately frozen in the liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier according to our proprietary method developed before. The resultant composite particles with phenytoin prepared by using acetonitrile (4N-SFD-MeCN system) were deeply characterized compared to those using aqueous solution (4N-SFD-aqua system) from morphological and physicochemical perspectives. The characteristic porous structure was observed in 4N-SFD-MeCN particles as well as 4N-SFD-aqua particles. However, it was found that the size and quantity of pore in 4N-SFD-MeCN particles were smaller than those of 4N-SFD-aqua particles. As a result, the former particles had 2- to 3-times smaller specific surface area than the latter particles independent of the type of carrier loaded. The slight difference of release profiles from the particles prepared between both systems was discussed from the microscopically structural viewpoint. In addition, ciclosporin was applied to organic solvent SFD system because this drug was poorly water soluble and cannot be applied to conventional aqueous SFD system. The release profiles from SFD particles were dramatically improved compared to the bulk material, suggesting that the new SFD technique using organic solvent has potential to develop the novel solubilized formulation for poorly water-soluble active pharmaceutical ingredients (APIs).

Influence of compression pressure and velocity on tablet sticking.

A rotary tablet machine fitted with 8-mm diameter flat-faced punches was used to measure scraper pressure (SCR), a type of shear stress, to evaluate sticking behavior. The shear stress between the surfaces of the tablet and lower punch was determined using an SCR detection system. Mean surface roughness (R(a)) of tablets, measured by a scanning laser-microscope, was used to estimate the magnitude of sticking. Tablet tensile strength tended to increase with compression pressure at either of the tablet production velocities tested, which was consistent with previous reports. SCR decreased with increasing compression pressure for samples at all compression velocities, and showed a tendency to increase with binder concentration. SCR also tended to increase with compression velocity for samples at all compression pressures, suggesting that the frequency of tablet sticking increased as compression velocity increased. R(a) associated with sticking increased with SCR, indicating that the adhesive force between the particles of the tablet surface and the lower punch surface plays an important role in sticking.

Evaluation of additives required for periodontal disease formulation using basic fibroblast growth factor.

To design a suitable periodontal disease formulation using basic fibroblast growth factor (bFGF), legally available thickeners were evaluated focusing on their viscosity, extrusive force from a syringe, flow property and inertness to bFGF. Thirteen candidate thickeners showed appropriate viscosity (about 1×104 mPa·s), and further evaluations were conducted on them. Flow property was evaluated by the tilting test tube method. As a result, most thickener solutions with the optimum viscosity showed appropriate flow time (about 100 s) and the flow time did not depend on thickener concentration, whereas the extrusive force from a syringe depended on thickener concentration despite the thickener type and grade. Thickener solutions of 2-3% showed ideal result (10-20 N) and thickener solutions prepared outside of the concentration range (2-3%) were found to show unsuitable extrusive force. Consequently, to obtain required properties for a dental drug formulation, thickener solutions needed to show adequate viscosity (about 1×104 mPa·s) at 2-3% thickener concentration. In addition, several types of cellulose derivatives showed inertness to the bFGF because of their structure, without strong ionic dissociable groups, and neutral pH. Overall, the present work demonstrates that some water-soluble cellulose derivatives, such as hydroxypropylcellulose (HPC) and hydroxyethylcellulose (HEC), were suggested to have required properties for a dental drug formulation including bFGF.

[Evaluation of the binding affinity and RNA interference of low-molecular-weight chitosan/siRNA complexes using an imaging system].

Chitosan is one of the attractive non-viral carriers for gene delivery including siRNA. However, common chitosan, which has a relatively high molecular weight, is insoluble in water, which might make it difficult to apply clinically. In this study, we investigated the efficacy of low-molecular-weight chitosan (LMWC), which is soluble in water, as a carrier for siRNA delivery. To evaluate the binding affinity and RNA interference (RNAi) of LMWC/siRNA complexes, a multi-well imaging system (IVIS) was adapted. CT26 cells stably expressing firefly luciferase (CT26/Luc cells) were established to evaluate RNAi. Evaluation of RNAi using lipofectamine(TM) 2000 was carried out by employing a luminometer with cell lysis and IVIS without cell lysis. The results were closely correlated, suggesting the advantages of the multi-well imaging system regarding screening, the visualization of results, and nondestructive evaluation. Fluorescence generated by ethidium bromide intercalated in the double strand of siRNA was markedly quenched at a higher ratio of LMWC to siRNA (N/P) and lower pH. Evaluation of the particle size and zeta potential of LMWC/siRNA complexes also indicated the higher binding affinity of LMWC with siRNA. At N/P=300 and pH 6.5, which satisfied the high-level binding affinity of LMWC with siRNA, significantly lower luminescence was detected in CT26/Luc cells treated with LMWC/siRNA compared with those treated with LMWC alone, suggesting the presence of RNAi. These results suggested that LMWC may be an effective carrier for siRNA delivery, and that the multi-well imaging system may be a powerful tool to evaluate the binding affinity and RNAi.

Application of supercritical fluid to preparation of powders of high-molecular weight drugs for inhalation.

The application of supercritical carbon dioxide to particle design has recently emerged as a promising way to produce powders of macromolecules such as proteins and genes. Recently, an insulin powder for inhalation was approved by authorities in Europe and the USA. Other macromolecules for inhalation therapy will follow. In the 1990s proteins were precipitated with supercritical CO(2) from solutions in an organic solvent such as dimethylsulfoxide, which caused significant unfolding of protein. Since 2000, aqueous solutions of proteins and genes have generally been used with a cosolvent such as ethanol to precipitate in CO(2). Operating conditions such as temperature, pressure, flow rates, and concentration of ingredients affect the particle size and integrity of proteins or genes. By optimizing these conditions, the precipitation of proteins and genes with supercritical CO(2) is a promising way to produce protein and gene particles for inhalation.

[Drug delivery to the colon using novel one-step, dry-coated tablets (OSDrC)].

One-step dry-coated tablets (OSDrC), which are useful as colon-targeting drugs, were prepared using Eudragit L 100-55 (Eud-L) and chitosan (Chit) as an outer layer. The lag time of OSDrC with an outer layer of Eud-L : Chit at a ratio of 3 : 1 in each test medium was greater than the gastric emptying time in the first fluid simulating the stomach and was greater than the small intestine transit time in phosphate buffer (pH 7.4) simulating the small intestine. Drug-release profiles of OSDrC were evaluated under test conditions considering the amount of gastric acid and bile acid, as well as the amount of fluid in the colon. The lag time of OSDrC was greater than the gastric emptying time in test medium simulating the stomach and greater than the small intestine transit time in test medium simulating the small intestine, although it was affected by the amount of gastric acid and bile acid. Drug release from OSDrC was completed within the colonic transit time in the test medium simulating the colon, although it was affected by the amount of fluid in the colon. Therefore the prepared OSDrC were found to permit drug delivery to the colon.

[Local and systemic delivery of high-molecular weight drugs by powder inhalation].

The pulmonary route has recently attracted attention as a noninvasive administration route for peptide and protein drugs, and an insulin powder for inhalation was approved by authorities in Europe and the USA. The present study examined usefulness of insulin and gene powders for systemic and local inhalation therapy. We prepared several dry insulin powders by spray drying to examine the effect of additives on insulin absorption. Citric acid appears to be a safe and potent absorption enhancer for insulin in dry powder. However, in the powder with citric acid (MIC0.2 SD) insulin was unstable compared with the other powders examined. To improve insulin stability, a combination of insulin powder and citric acid powder was prepared (MIC Mix). MIC Mix showed hypoglycemic activity comparable to MIC0.2 SD while the insulin stability was much better than that of MIC SD. Next, dry insulin powders with mannitol were prepared with supercritical carbon dioxide (SCF); the powder thus prepared reduced blood glucose level rapidly and was more effective than that prepared by spray drying. Chitosan-pDNA complex powders as a pulmonary gene delivery system were also prepared with SCF and their in vivo activity was evaluated. The addition of chitosan suppressed the degradation of pCMV-Luc during preparation and increased the storage stability. The luciferase activity in mouse lung was evaluated after pulmonary administration of the powders. The chitosan-pDNA powder with an N/P ratio=5 increased the luciferase activity to 27 times that of the pCMV-Luc solution. These results suggest that gene powder with chitosan is a useful pulmonary gene delivery system.

[Preparation and release profile of colon-targeting drug delivered as novel one-step dry-coated tablets (OSDrC)].

One-Step Dry-Coated tablets (OSDrC) of a colon-targeting drug were prepared using Eudragit L 100-55 (Eud-L) and chitosan (Chit) as the outer layer. Lag time in the 1st fluid, which simulated the stomach, was affected by differences in the pores occurring as a result of Chit dissolution. The dissolution rate of Chit was decreased by the addition of Eud-L. On the other hand, lag times in phosphate buffer (pH 7.4) simulating the small intestine, and in the 2nd fluid simulating the colon, were affected by differences in the pores occurring as a result of Eud-L dissolution and Chit swelling. The lag time of OSDrC with an outer layer of Eud-L:Chit at a ratio of 3:1 in each test medium was greater than the gastric emptying time in the 1st fluid and the small intestine transit time in phosphate buffer (pH 7.4). Furthermore, lag times were similar when test media were changed sequentially. Therefore, it is possible to deliver colon-targeting drugs as OSDrC with an outer layer of Eud-L:Chit at 3:1.

Synthesis and properties of polysaccharide prodrugs of 5-aminosalicylic acid as potential colon-specific delivery systems.

The drug release of the polymer prodrugs of 5-aminosalicylic acid (5-ASA) was not only dependent on the property of the polymers but also dependent on the solubility of the prodrugs. We prepared several polysaccharide prodrugs of 5-ASA to examine the effect of solubility of prodrugs on the release characteristics of 5-ASA in the gastrointestinal contents of rats. The amide prodrug, chitosan-5-ASA (ChT-5-ASA), did not release the 5-ASA in the cecal and colonic contents. The ester prodrugs, hydroxypropyl cellulose-5-ASA (HPC-5-ASA), being poor solubility in 0.05mol/l acetic acid solution also did not release the 5-ASA in any of gastrointestinal contents of rats. Whereas the 5-ASA release from cyclodextrins-5-ASA (CyDs-5-ASA) in cecal and colonic contents was significantly higher than that in stomach and small intestine contents. And furthermore, with the decrease in the degree of substitution, the solubility of CyD-5-ASA increased, and the release of 5-ASA in the gastrointestinal contents was also higher at the same time interval of incubation. When the ratio of cyclodextrin (CyD) and 5-formylaminosalicylic acid (5-fASA), a precursor of 5-ASA prodrugs, was 1:10, CyD-5-ASA was very slightly soluble, and no release of 5-ASA was observed within 48h in gastrointestinal contents. The present results suggested that the ester prodrugs of 5-ASA with certain solubility could release 5-ASA in the cecal and colonic contents of rat.

Colon-specific drug delivery systems based on cyclodextrin prodrugs: in vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates.

AIM: To investigate the release of cyclodextrin-5-aminosalicylic acid (CyD-5-ASA) in cecum and colon. METHODS: An anti-inflammatory drug 5-ASA was conjugated onto the hydroxyl groups of alpha-, beta- and gamma-cyclodextrins (CyDs) through an ester linkage, and the in vivo drug release behavior of these prodrugs in rat's gastrointestinal tract after the oral administration was investigated. RESULTS: The 5-ASA concentration in the rat's stomach and small intestine after the oral administration of CyD-5-ASA conjugate was much lower than that after the oral administration of 5-ASA alone. The lower concentration was attributable to the passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specific in the cecum and colon. The oral administration of CyD-5-ASA resulted in lower plasma and urine concentration of 5-ASA than that of 5-ASA alone. CONCLUSION: CyD-5-ASA conjugates may be used as prodrugs for colon-specific drug delivery system.

Stability of chitosan-pDNA complex powder prepared by supercritical carbon dioxide process.

The present study examined the stability of a gene in powders prepared with supercritical carbon dioxide (CO(2)) from the viewpoints of the ternary structure of DNA and in vivo transfection potential. An aqueous chitosan-pCMV-Luc complex solution containing mannitol was injected into the stream of a supercritical CO(2)/ethanol admixture to precipitate a gene powder. The obtained gene powders and gene solutions were placed in stability chambers at 25 or 40 degrees C for 4 weeks. The integrity and transfection potency of the gene were examined by electrophoresis and in vivo pulmonary transfection study in mice. The supercritical CO(2) process decreased the supercoiled DNA during the manufacturing process; however, the decrease in the remaining supercoiled and open circular DNA in the powders during storage was much slower than that in solutions. In addition, the powders had higher transfection potency than the solutions containing the same amount of DNA. The effect of chitosan on the stability of DNA in solutions was not obvious in the solutions but it improved the stability of DNA in powders during manufacturing and storage. Thus, a gene powder with a cationic vector is a promising ready-to-use formulation for inhalation therapy of pulmonary diseases.

Evaluation of novel one-step dry-coated tablets as a platform for delayed-release tablets.

Using a novel one-step dry-coated tablets (OSDRC) manufacturing method, which we have recently invented, we evaluated the possibility of its application to delayed-release tablets. The manufacturing method for OSDRC is different from conventional methods in that dry-coated tablets can be made with only one process. One of the major advantages of OSDRC is that we can expect to produce tablets, which always contain the core exactly in the center of the whole tablet. This characteristic means that the thickness of outer layer is constantly uniform, which is difficult to achieve with the conventional dry-coated tablets. The effects of different outer layer thicknesses and various compression pressures were examined using HPMC to evaluate OSDRC applicability to delayed-release tablets. We proved that the lag-time can be adjusted only by changing the thickness of the outer layer without any arrangement of its ingredients, which is quite different from the conventional approach. Further, the lag-time of each OSDRC prepared in the 100-200 MPa compression pressure range was almost the same, indicating the lag-time of OSDRC under these compression pressures does not vary. The release rate of the drug (acetaminophen) from the OSDRC with 0.5 and 1.0 mm outer layer thicknesses was almost constant independent of compression pressure. On the other hand, the release rate of the OSDRC with a 2.0 mm outer layer thickness was delayed compared to that of other thicknesses. That is, in the tablets with 2.0 mm outer layer thickness, the release rate declined since its outer layer thickness was sufficient to form a gel-layer. In conclusion, OSDRC could be a platform for delayed-release tablets, which do not utilize the conventional method used for dry-coated tablets.

Improvement of insulin absorption from intratracheally administrated dry powder prepared by supercritical carbon dioxide process.

The purpose of this study was to improve insulin absorption from dry powder after administration in lung without an absorption enhancer. The dry powders, with mannitol as a carrier, were prepared with or without an absorption enhancer (citric acid) by supercritical carbon dioxide (SCF) and spray drying (SD) processes. Insulin powder was precipitated from dimethyl sulfoxide and aqueous solutions by dispersing the insulin solutions from parallel and V-type nozzles, respectively, into supercritical carbon dioxide, which is an antisolvent for insulin. In vitro aerosol performance was evaluated with a cascade impactor. Insulin powder containing citric acid prepared by the SCF method (MIC SCF) showed improved inhalation performance compared with insulin powder prepared by the SD process, although the particle size of the former powder was larger than that in powders prepared by SD. Insulin absorption was estimated from the change in plasma glucose level. The blood glucose level after administration of the insulin powder without citric acid prepared by the SCF process (MI SCF) decreased rapidly, and a significant difference was observed for areas under the curve of change in plasma glucose concentration versus time (AUCs) between MI SCF and the insulin powder without citric acid prepared by the SD process (MI SD). These results suggest that the SCF technique would be useful to prepare dry powders suitable for inhalation.

Development of polymer film dosage forms of lidocaine for buccal administration: II. Comparison of preparation methods.

In previous studies, we prepared film dosage forms of lidocaine (LC) with hydroxypropylcellulose (HPC) as a film base using the solvent evaporation (SE) method. However, from the viewpoint of environmental issues, a reduction in organic solvent use in pharmaceutical and other industries is required. In this study, we prepared the LC films by direct compression of the physical mixture (DCPM method) and direct compression of the spray dried powder (DCSD method). Magnesium stearate, which was required as a lubricant for direct compression, showed no effect on the LC release rate. The LC release rate (%/h) was independent of the compression pressure, but a higher pressure was preferable to easily remove the film from the punches. An increase in the film weight decreased the LC release rate expressed in %/h, whereas no significant effect of film weight was observed on the LC release rate from unit surface area expressed in mg/h/cm(2). The LC release rate (%/h) was independent of the LC content, suggesting that the LC release rate (mg/h) can be quantitatively controlled by changing the LC content in the formulation. The LC release rate and penetration rate were affected by the preparation method; that is, DCPM method < DCSD method < SE method. The LC penetration rates through excised hamster oral mucosa were linearly correlated to the release rate of un-ionized LC, which was estimated by the LC release rate multiplied by the un-ionized fraction of LC for the HPC film dosage form.