Liposphere Local Anesthetic Timed-Release for Perineural Site Application

Purpose. This investigation determines the drug delivery capacity of Lipospheres, which are drug-containing solid-filled vesicles made of triglyceride with a phospholipid outer covering, to release local anesthetic in vitro and to produce sustained peripheral nerve block in vivo. Methods. The local anesthetic, bupivacaine, was loaded into Lipospheres in several dosage forms, characterized, and measured for in vitrorelease. In rats, Lipospheres were administered into a large space between muscle layers surrounding the sciatic nerve to assess sensory and motor block in vivo. Results. The particle size of Lipospheres was determined to be between 5 and 15 m, with over 90% surface phospholopid. Lipospheres released bupivacaine over two days under ideal sink conditions. Liposphere nerve application produced dose-dependent and reversible block. Indeed, sustained local anesthetic block (SLAB) was observed for 1–3 days in various in vivo tests: a) Hind paw withdrawal latency to noxious heat was increased over 50% for 96 hr period after application of 3.6% or 5.6% bupivacaine-Lipospheres. The 3.6% and 5.6% doses were estimated to release bupivacaine at 200 and 311 g drug/ hr, respectively, based on release spanning 72 hr. Application of 1.6% bupivacaine-Lipospheres increased withdraw latency 25–250% but for only a 24 hr duration; b) Similarly, vocalization threshold to hind paw stimulation was increased 25–50% for 72 hr following application of 3.6% bupivacaine-Lipospheres; c) Finally, sensory blockade outlasted or equaled corresponding motor block duration for all Liposphere drug dosages. Conclusions. Liposphere delivery of local anesthetic drugs may be well suited for site-specific pharmacotherapy of neural tissue to produce SLAB. Dose-dependent effects in duration of action may include lipophilic tissue storage.     

Local anesthetic lidocaine delivery system: chitosan and hyaluronic acid-modified layer-by-layer lipid nanoparticles

Context: Transdermal local anesthesia is one of the most applied strategies to avoid systemic adverse effects; there is an appealing need for a prolonged local anesthetic that would provide better bioavailability and longer pain relief with a single administration.

Objective: Layer-by-layer (LBL) technique was used in this study to explore a nanosized drug delivery system for local anesthetic therapy.

Materials and methods: LBL-coated lidocaine-loaded nanostructured lipid nanoparticles (LBL-LA/NLCs) were prepared and characterized in terms of particle size (PS), zeta potential, drug encapsulation efficiency (EE), in vitro skin permeation and in vivo local anesthetic studies.

Results: Evaluation of the in vitro skin permeation and in vivo anesthesia effect illustrated that LBL-LA/NLCs can enhance and prolong the anesthetic effect of LA.

Discussion and conclusion: LBL-LA/NLCs could function as a promising drug delivery strategy for overcoming the barrier function of the skin and could deliver anesthetic through the skin with sustained release behavior for local anesthetic therapy.     

Prolonged Local Anesthetic Action Through Slow Release from Poly(Lactic Acid Co Castor Oil)

Purpose  To evaluate a new formulation of bupivacaine loaded in an injectable fatty acid based biodegradable polymer poly(lactic acid co castor oil) in prolonging motor and sensory block when injected locally. Materials and methods  The polyesters were synthesized from dl-lactic acid and castor oil with feed ratio of 4:6 and 3:7 w/w. Bupivacaine was dispersed in poly(fatty ester) liquid and tested for drug release in vitro. The polymer p(DLLA:CO) 3:7 loaded with 10% bupivacaine was injected through a 22G needle close to the sciatic nerve of ICR mice and the duration of sensory and motor nerve blockade was measured. Results  The dl-lactic acid co castor oil p(DLLA:CO) 3:7 released 65% of the incorporated bupivacaine during 1 week in vitro. Single injection of 10% bupivacaine loaded into this polymer caused motor block that lasted 24 h and sensory block that lasted 48 h. Conclusion  Previously we developed a ricinoleic acid based polymer with incorporated bupivacaine which prolonged anesthesia to 30 h. The new polymer poly(lactic acid co castor oil) 3:7 provides slow release of effective doses of the incorporated local anesthetic agent and prolongs anesthesia to 48 h.     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Drug Release from a Novel <Emphasis Type="BoldItalic">In Situ</Emphasis> Forming Drug Delivery System

Purpose The objective of this work was to investigate the influence of various preparation and formulation parameters on the in vitro and in vivo release of bupivacaine hydrochloride from an injectable in situ forming microparticle system (ISM). Methods The in vitro drug release of ISM was investigated as a function of various formulation and process parameters and was compared to the drug release from in situ forming implants and conventional microparticles. In vivo studies were carried out in male Sprague–Dawley rats. Results Upon contact with an aqueous medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems was reduced with decreasing polymer phase/external oil phase ratio. An advantage of the ISM system compared to in situ implant systems was the significantly reduced burst effect, resulting in drug release profiles comparable to microparticles prepared by conventional methods. The in vivo drug release studies were in good agreement with the in vitro drug release. With the ISM system, the analgesic effect of the bupivacaine hydrochloride was prolonged when compared to the injection of a drug solution or drug-polymer solution. Conclusions ISM are an attractive alternative for parenteral drug delivery systems.     

Poly(dl:Lactic Acid-Castor Oil) 3:7-Bupivacaine Formulation: Reducing Burst Effect Prolongs Efficacy In Vivo

Prolonged analgesia may be achieved using a single injection of slow-release local anesthetic formulation. The study objective was to improve the efficacy of a previously reported formulation comprising 10% bupivacaine in poly(dl:lactic acid co castor oil) 3:7. The polymer was loaded with 15% bupivacaine and injected through a 22G needle close to the sciatic nerve of ICR mice. Sensory and motor nerve blockade were measured. The efficacy and toxicity of the polymer–drug combination were determined. Sixty percent of the incorporated bupivacaine was released during 1 week in vitro. During in vitro release no burst effect was seen, suggesting low toxicity of the formulation. Single injection of 0.1 mL of 15% polymer-bupivacaine formulation caused motor block that lasted 64 h and sensory block that lasted 96 h. The MTD of the polymer–drug formulation was established as 0.175 mL. Microscopic examination of the injection sites revealed reversible nerve inflammation and normal internal organs. The polymer poly(dl:lactic acid co castor oil) 3:7 is a safe carrier for prolonged activity of bupivacaine up to 96 h. The increase of drug load in the formulation reduces the drug release rates due to stronger polymer–drug interactions and higher overall hydrophobicity of the formulation     

Mexiletine has a local anesthetic effect on sciatic nerve blockade in rats

Mexiletine is an antiarrhythmic drug that has a Na⁺ channel blocking activity. The aim of the present study was to evaluate whether mexiletine had a local anesthetic effect as assessed by sciatic nerve blockade. Thus, the potency and duration of action of mexiletine on sciatic nerve blockade in terms of motor function and nociception were evaluated. Two local anesthetics, bupivacaine and lidocaine, were used as controls. Mexiletine produced a dose‐related local anesthetic effect on sciatic nerve blockade. The rank potency was bupivacaine >lidocaine >mexiletine (P<0.05 for each comparison). On an equi‐potent basis, the rank duration of action was bupivacaine>mexiletine>lidocaine (P<0.05 for each comparison). Co‐administration of mexiletine with bupivacaine produced an additive effect on sciatic nerve blockade. In conclusion, mexiletine had a local anesthetic effect on sciatic nerve blockades of motor function and nociception. Co‐administration of mexiletine with bupivacaine produced an additive effect on sciatic nerve blockade. Drug Dev. Res. 67:905–909, 2006. © 2007 Wiley‐Liss, Inc.     

Polyvinyl Alcohol–Methyl Acrylate Copolymers as a Sustained-Release Oral Delivery System

Low crystalline and crystalline polyvinyl alcohol–methyl acrylate (PVA-MA) copolymers were examined, because of their excellent flow and compressibility properties, as matrices for sustained-release tablets using phenylpropanolamine hydrochloride (PPA.HC1) as a model drug. Crystallinity of the copolymer affected the release characteristics from the tablet. Tablets made with low-crystalline PVA-MA provided sustained release of PPA, both in vitro and in vivo in dogs. PPA absorption from the low-crystalline PVA-MA tablet formulation was biphasic. An initial rapid phase was followed by a second, slower absorption phase which continued over 16 hr. Plasma PPA concentrations then declined with a half-life roughly parallel to the oral immediate-release half-lives. Oral bioavailability from the low-crystalline PVA-MA tablet formulation was 78.8 ± 3.9%.     

Imperatorin sustained-release tablets: <Emphasis Type="Italic">In Vitro</Emphasis> and pharmacokinetic studies

We prepared and evaluated imperatorin (IMP) sustained-release tablets. IMP is an active compound in Angelica dahuricae, a Chinese herbal medicine. We used different polymers, such as hydroxypropyl methylcellulose (HPMC K4M, K15M, and K100M), carbopol 934P, sodium carboxymethyl cellulose (CMC-Na), and their combinations to prepare the matrix tablets and achieve the desired sustained release profile. The in vitro release profiles of these formulations were examined and fit to various kinetic release models. We also tested the effects of polymer combination ratios on the in vitro release rate. In vivo studies were performed for the optimized formulation in six beagle dogs, and pharmacokinetic parameters were compared with plain IMP tablets. IMP sustained-release tablets exhibited a more sustained plasma concentration than the plain tablets, with a relative bioavailability of 127.25%. The in vitro releases rates and in vivo absorption correlated for the initial 8 hours. These results demonstrate that the sustained-release tablet system can effectively control the release of IMP.     

口服缓释制剂体内外相关性评价方法研究进展

《药物评价研究》杂志是由中国药学会和天津药物研究院共同主办的国家级期刊,双月刊,国内外公开发行。办刊宗旨:报道药物评价工作实践,推动药物评价方法研究,开展药物评价标准或技术探讨,促进药物评价与研究水平的提高,为广大药物研究人员提供交流平台。内容与栏目:针对药物及其制剂的评价规范以及药学评价、安全性评价、药效学评价、药物代谢动力学评价、临床评价、     

VEGF-controlled release within a bone defect from alginate/chitosan/PLA-H scaffolds

VEGF and its receptors constitute the key signaling system for angiogenic activity in tissue formation, but a direct implication of the growth factor in the recruitment, survival and activity of bone forming cells has also emerged. For this reason, we developed a composite (alginate/chitosan/PLA-H) system that controls the release kinetics of incorporated VEGF to enhance neovascularization in bone healing. VEGF release kinetics and tissue distribution were determined using iodinated (¹²⁵I) growth factor. VEGF was firstly encapsulated in alginate microspheres. To reduce the high in vitro burst release, the microspheres were included in scaffolds. Matrices were prepared with alginate (A-1, A-2), chitosan (CH-1, CH-2) or by coating the CH-1 matrix with a PLA-H (30 kDa) film (CH-1-PLA), the latter one optimally reducing the in vitro and in vivo burst effect. The VEGF in vitro release profile from CH-1-PLA was characterized by a 13% release within the first 24 h followed by a constant release rate throughout 5 weeks. For VEGF released from composite scaffolds in vitro, bioactivity was maintained above 90% of the expected value. Despite the fact that the in vivo release rate was slightly faster, a good in vitro–in vivo correlation was found. The VEGF released from CH-1 and CH-1-PLA matrices implanted into the femurs of rats remained located around the implantation site with a negligible systemic exposure. These scaffolds provided a bone local GF concentration above 10 ng/g during 2 and 5 weeks, respectively, in accordance to the in vivo release kinetics. Our data show that the incorporation of VEGF into the present scaffolds allows for a controlled release rate and localization of the GF within the bone defect.     

Enhancing and sustaining the topical ocular delivery of fluconazole using chitosan solution and poloxamer/chitosan in situ forming gel

Fungal keratitis is a serious disease that can lead to loss of vision. Unfortunately, current therapeutic options often result in poor bioavailability of antifungal agents due to protective mechanisms of the eye. The aim of this work was to evaluate the potential of a chitosan solution as well as an in situ gel-forming system comprised of poloxamer/chitosan as vehicles for enhanced corneal permeation and sustained release of fluconazole (FLU). For this, in vitro release and ex vivo corneal permeation experiments were carried out as a function of chitosan concentration from formulation containing the chitosan alone and combined with the thermosensitive polymer, poloxamer. Microdialysis was employed in a rabbit model to evaluate the in vivo performance of the formulations. The in vitro release studies showed the sustained release of FLU from the poloxamer/chitosan formulation. Ex vivo permeation studies across porcine cornea demonstrated that the formulations studied have a permeation-enhancing effect that is independent of chitosan concentration in the range from 0.5 to 1.5% w/w. The chitosan solutions alone showed the greatest ex vivo drug permeation; however, the poloxamer/chitosan formulation presented similar in vivo performance than the chitosan solution at 1.0%; both formulations showed sustained release and about 3.5-fold greater total amount of FLU permeated when compared to simple aqueous solutions of the drug. In conclusion, it was demonstrated that both the in situ gelling formulation evaluated and the chitosan solution are viable alternatives to enhance ocular bioavailability in the treatment of fungal keratitis.     

Formulation and Characterization of Immunoreactive Tetanus Toxoid Biodegradable Polymer Particles

Poly lactide-co-glycolide and polylactide polymer particles entrapping immunoreactive tetanus toxoid (TT) were prepared with a view to developing a single shot controlled release vaccine formulation. Denaturation of TT by dichloromethane (DCM) during primary emulsification stage of particle formulation was minimized by incorporation of an optimal amount of rat serum albumin (RSA) in the internal aqueous phase. Incorporation of RSA as a stabilizer during the primary emulsification stage of polymer particle formulation protected the immunoreactivity of TT, enhanced its encapsulation efficiency and also led to uniform polymer particle formation. Use of sonication, both during primary and secondary emulsification processes, resulted in formation of nanoparticles whereas microparticles were formed when the secondary emulsion was carried out by homogenization. Immunoreactive TT particles made from different polymers incorporating stabilizers released antigen continuously for more than four months in vitro. Single injection of both type of particles encapsulating stabilized TT elicited anti-TT antibody titers in rats for more than five months, which was higher than that obtained with TT injected in saline. Anti-TT antibody titers in vivo were in accordance with the in vitro release characteristics of immunoreactive TT from the particles. Immune responses with hydrophobic polymer particles were better than those made using hydrophilic polymers. These results indicate the importance of protecting the immunoreactivity of TT during formation of polymer particles for sustained and improved antibody response.     

Formulation of novel sustained release rifampicin-loaded solid lipid microparticles based on structured lipid matrices from Moringa oleifera

Abstract

Objectives: To formulate sustained release rifampicin-loaded solid lipid microparticles (SLMs) using structured lipid matrices based on Moringa oil (MO) and Phospholipon 90G (P90G).

Methods: Rifampicin-loaded and unloaded SLMs were formulated by melt homogenization and characterized in terms of particle morphology and size, percentage drug content (PDC), pH stability, stability in simulated gastric fluid (SGF, pH 1.2), minimum inhibitory concentration (MIC) and in vitro release. In vivo release was studied in Wistar rats.

Results: Rifampicin-loaded SLMs had particle size range of 32.50?±?2.10 to 34.0?±?8.40?μm, highest PDC of 87.6% and showed stable pH. SLMs had good sustained release properties with about 77.1% release at 12?h in phosphate buffer (pH 6.8) and 80.3% drug release at 12?h in simulated intestinal fluid (SIF, pH 7.4). SLMs exhibited 48.51% degradation of rifampicin in SGF at 3?h, while rifampicin pure sample had 95.5% degradation. Formulations exhibited MIC range of 0.781 to 1.562, 31.25 to 62.5 and 6.25 to 12.5?μg/ml against Salmonella typhi, Escherichia coli, and Bacillus subtilis respectively and had higher in vivo absorption than the reference rifampicin (p?<?0.05).

Conclusion: Rifampicin-loaded SLMs could be used once daily for the treatment tuberculosis.     

Facile design of lidocaine-loaded polymeric hydrogel to persuade effects of local anesthesia drug delivery system: complete in vitro and in vivo toxicity analyses

The principal goal of the present investigation was to enterprise new and effective drug delivery vesicle for the sustained delivery of local anesthetic lidocaine hydrochloride (LDC), using a novel combination of copolymeric hydrogel with tetrahydroxyborate (COP–THB) to improve bioactivity and therapeutic potential. To support this contention, the physical and mechanical properties, rheological characteristics, and component release of candidate formulations were investigated. An optimized formulation of COP–THB containing LDC to an upper maximum concentration of 1.5% w/w was assessed for drug crystallization. The biocompatibility of the prepared COP–THB hydrogel was exhibited strong cell survival (96%) and growth compatibility on L929 fibroblast cell lines, which was confirmed by using methods of MTT assay and microscopic observations. The COP–THB hydrogel release pattern is distinct from that of COP–THB/LDC hydrogels by the slow-release rate and the low percentage of cumulative release. In vivo evaluations were demonstrated the anesthetic effects and toxicity value of treated samples by using mice models. In addition, COP–THB/LDC hydrogels significantly inhibit in vivo tumor growth in mice model and effectively reduced it is in vivo toxicity. The pharmacological evaluation showed that encapsulation of LDC in COP–THB hydrogels prolonged its anesthetic action with favorable in vitro and in vivo compatibility. This novel design may theoretically be used in promising studies involving the controlled release of local anesthetics.

Highlights

• Development a modified sustained release system for the local anesthetic lidocaine.
• PVP-THB hydrogel to improve the pharmacological properties of the drug and their anesthetic activities.
• Profiles of PVP-THB/LDC showed that the effective release of associated lidocaine.
• This new formulation could potentially be used in future local anesthetics.

     

Biocompatibility of an Injectable In Situ Forming Depot for Peptide Delivery

Poly(ethyleneglycol) 500 dimethylether (PEG500DME) was tested as a novel solvent for the manufacture of an injectable in situ forming depot (ISFD) containing poly(d,l-lactide-co-glycolide) (PLGA). The sustained release of pasireotide from the ISFD was evaluated in vitro and in vivo. Furthermore, the local tolerability of the delivery system using PEG500DME was investigated in subcutaneous (s.c.) tissue over 48 days. A flow-through cell was used to determine the in vitro drug release from the ISFD in comparison to a peptide suspension without polymer. The biocompatibility as well as the pharmacokinetic profile of the ISFD was investigated in rabbits. A prolonged peptide release over at least 48 days with an initial burst lower than 1% was observed in vitro for the ISFD compared to the suspension without polymer. A similar tissue response as it was observed for other common PLGA delivery systems was found upon histopathological examination of tissue from the administration site in rabbits. A sustained release of at least 48 days in vivo confirmed the in vitro observation including the low initial plasma concentration levels. Two ISFDs with different peptide loads were used to correlate the in vitro and in vivo data (IVIVC). Overall, the functionality of the ISFD containing PEG500DME as a novel solvent was demonstrated in vitro and in vivo. In addition, the local tolerability of the system confirmed the biocompatibility of PEG500DME in parenteral depots.     

A Biodegradable Injectable Implant Sustains Systemic and Ocular Delivery of an Aldose Reductase Inhibitor and Ameliorates Biochemical Changes in a Galactose-Fed Rat Model for Diabetic Complications

Purpose. To fabricate and characterize in vitro and in vivo performance of a sustained release biodegradable implant for N-4-(benzoylaminophenylsulfonyl glycine) (BAPSG), a novel aldose reductase inhibitor. Methods. The ability of BAPSG to inhibit aldose reductase activity and glucose-induced vascular endothelial growth factor (VEGF) expression was assessed in a retinal pigment epithelial cell line (ARPE-19). A poly (DL-lactic-co-glycolic acid) implant containing 50% w/w BAPSG was fabricated and characterized for drug loading, in vitro drug release, and the thermal behavior of the drug and the polymer. Implants were injected subcutaneously into a galactose-fed diabetic rat model and cataract scores, plasma and tissue drug levels, galactitol levels in the lens and the retina, glutathione levels in the plasma, lens, cornea and retina and VEGF expression in the retina were determined on or until 18 days. Results. BAPSG inhibited aldose reductase activity and reduced VEGF expression in ARPE-19 cells. Implants (1 × 4 mm), with a loading efficiency of 106 7% for BAPSG, were fabricated. Upon implant fabrication, while the glass transition temperature of the polymer decreased, the melting point of the drug was not affected. In vivo drug release correlated well with in vitro release, with 44% drug release occurring in vivo by the end of 18 days. The implant reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats. Conclusions. An injectable biodegradable implant of BAPSG sustained drug release in vitro and in vivo, and reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats.     

Dibucaine in Ionic-Gradient Liposomes: Biophysical,Toxicological, and Activity Characterization

Administration of local anesthetics is one of the most effective pain control techniques for postoperative analgesia. However, anesthetic agents easily diffuse into the injection site, limiting the time of anesthesia. One approach to prolong analgesia is to entrap local anesthetic agents in nanostructured carriers (e.g., liposomes). Here, we report that using an ammonium sulphate gradient was the best strategy to improve the encapsulation (62.6%) of dibucaine (DBC) into liposomes. Light scattering and nanotracking analyses were used to characterize vesicle properties, such as, size, polydispersity, zeta potentials, and number. In vitro kinetic experiments revealed the sustained release of DBC (50% in 7 h) from the liposomes. In addition, in vitro (3T3 cells in culture) and in vivo (zebrafish) toxicity assays revealed that ionic-gradient liposomes were able to reduce DBC cyto/cardiotoxicity and morphological changes in zebrafish larvae. Moreover, the anesthesia time attained after infiltrative administration in mice was longer with encapsulated DBC (27 h) than that with free DBC (11 h), at 320 μM (0.012%), confirming it as a promising long-acting liposome formulation for parenteral drug administration of DBC.     

Synthesis of nanocapsules blended polymeric hydrogel loaded with bupivacaine drug delivery system for local anesthetics and pain management

Local anesthetics are used clinically for the control of postoperative pain management. This study aimed to develop chitosan (CS) with genipin (GP) hydrogels as the hydrophilic lipid shell loaded poly(ε-caprolactone) (PC) nanocapsules as the hydrophobic polymeric core composites (CS-GP/PC) to deliver bupivacaine (BPV) for the prolongation of anesthesia and pain relief. The swelling ratio, in vitro degradation, and rheological properties enhancement of CS-GP/PC polymeric hydrogel. The incorporation of PC nanocapsules into CS-GP hydrogels was confirmed by SEM, FTIR, and XRD analysis. Scanning electron microscopy results demonstrated that the CS-GP hydrogels and CS-GP/PC polymeric hydrogels have a porous structure, the pore dimensions being non-uniform with diameters between 25 and 300 μm. The in vitro drug release profile of CS-GP/PC polymeric hydrogel has been achieved 99.2 ± 1.12% of BPV drug release in 36 h. Cellular viability was evaluated using the CCK-8 test on 3T3 fibroblast cells revealed that the obtained CS-GP/PC polymeric hydrogel with BPV exhibited no obvious cytotoxicity. The CS-GP/PC polymeric hydrogel loaded with BPV showed significant improvement in pain response compared to the control group animals for at least 7 days. When compared with BPV solution, CS-GP hydrogel and CS-GP/PC polymeric hydrogel improved the skin permeation of BPV 3-fold and 5-fold in 24 h, respectively. In vitro and in vivo results pointed out PC nanocapsules loaded CS-GP hydrogel can act as effective drug carriers, thus prolonging and enhancing the anesthetic effect of BPV. Histopathological results demonstrated the excellent biodegradability and biocompatibility of the BPV-loaded CS-GP/PC polymeric hydrogel system on 7, 14, and 21 days without neurotoxicity.

HIGHLIGHTS

• Preparation and characterization of CS-GP/PC polymeric hydrogel system.
• BPV-loaded CS-GP/PC exhibited prolonged in vitro release in PBS solution.
• Cytotoxicity of BPV-loaded CS-GP/PC polymeric hydrogel against fibroblast (3T3) cells.
• Development of CS-GP/PC a promising skin drug-delivery system for local anesthetic BPV.

     

The Solubility-Modulated Osmotic Pump: In Vitro/in Vivo Release of Diltiazem Hydrochloride

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem · HC1 as a model drug. Diltiazem · HC1 has an aqueous solubility >590 mg/ml (37°C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ ml; 37°C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of >80% of an initial diltiazem · HC1 load. Devices were prepared with cores that contained diltiazem · HC1 and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of 75% of the initial diltiazem HC1 load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.