RESUMO
In Part 1, we have introduced expandable gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. The expansion rate, post-expansion mechanical strength, and drug release rate were modeled for a dosage form containing 200â¯mg nilotinib. In the present part, the dosage form was prepared and tested in vitro to validate the models. Upon immersing in a dissolution fluid, the fibrous dosage form expanded at a constant rate to a normalized radial expansion of 0.5 by 4â¯h, and then formed an expanded viscoelastic mass of high strength. The drug was released at a constant rate over a day. For comparison, a particle-filled gelatin capsule with the same amount of nilotinib disintegrated almost immediately, and released eighty percent of the drug content in just 10â¯min. The experimental data validate the theoretical models of Part 1 reasonably.
RESUMO
At present, the efficacy and safety of many sparingly-soluble tyrosine kinase inhibitors (TKIs) delivered by the prevalent oral dosage forms are compromised by excessive fluctuations in the drug concentration in blood. To mitigate this limitation, in this four-part study gastroretentive fibrous dosage forms that deliver drug into the gastric fluid (and into the blood) at a controlled rate for prolonged time are presented. The dosage form comprises a cross-ply structure of expandable, water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC)-based fibers coated with a strengthening, enteric excipient. The intervening spaces between the coated fibers are solid annuli of drug particles, and low-molecular-weight HPMC and enteric excipients. The central regions of the annuli are open channels. In this part, models are developed for dosage form expansion, post-expansion mechanical strength, and drug release. The models suggest that upon immersing in a dissolution fluid, the fluid percolates the open channels, diffuses into the annuli and the coated fibers, and the dosage form expands. The expansion rate is inversely proportional, and the post-expansion mechanical strength proportional to the thickness of the strengthening coating. Drug particles are released from the annuli as the surrounding excipient dissolves. The drug release rate is proportional to the concentration of low-molecular-weight HPMC at the annulus/dissolution fluid interface. The dosage forms can be readily designed for expansion in a few hours, formation of a high-strength viscoelastic mass, and drug release at a constant rate over a day.
RESUMO
In this part, drug concentration in blood after ingesting slow-release gastroretentive fibrous dosage forms and immediate-release particulate forms is modeled. The tyrosine kinase inhibitor nilotinib, which is slightly soluble in low-pH gastric fluid but practically insoluble in pH-neutral intestinal fluid is used as drug. The models suggest that upon ingestion, the fibrous dosage form expands, is retained in the stomach for prolonged time, and releases drug into the gastric fluid at a constant rate. The released drug molecules flow into the duodenum with the gastric fluid, and are absorbed by the blood. The drug is eliminated from the blood by the liver at a rate proportional to its concentration. Eventually, the elimination and absorption rates will be equal, and the drug concentration in blood plateaus out. After the gastric residence time drug absorption stops, and the drug concentration in blood drops to zero. By contrast, after administering an immediate-release particulate dosage form the drug particles are swept out of the stomach rapidly, and drug absorption stops much earlier. The drug concentration in blood rises and falls without attaining steady state. The gastroretentive fibrous dosage forms enable a constant drug concentration in blood for drugs that are insoluble in intestinal fluids.
RESUMO
In this final part, the models of drug concentration in blood developed in Part 3 are validated on dogs. Both slow-release gastroretentive fibrous and immediate-release particulate dosage forms containing 200â¯mg nilotinib were tested. After administering, the fibrous dosage form expanded linearly with time in the stomach, to about 1.5 times the initial radius by 4â¯h. The expanded dosage form fractured after 10â¯h, and then passed into the intestines. The drug concentration in blood exhibited a broad peak with a maximum of 0.51⯵g/ml and a width at half-height of 10.2â¯h. By contrast, after administering the immediate-release capsule the drug concentration in blood exhibited a sharp peak with a maximum of 0.68⯵g/ml and a width at half-height of just 3.6â¯h. The experimental data validate the theoretical models reasonably. The gastroretentive fibrous dosage forms designed in this study enable a steady drug concentration in blood for increasing the efficacy and mitigating side effects of drug therapies.
RESUMO
Recently, we have shown in dogs that the gastric residence time of expandable fibrous dosage forms can be prolonged by coating the fibers with a semi-permeable, strengthening coating. In this work on pigs, the effect of the volume fraction of the coating, φc, on the expansion, mechanical strength, and gastric residence time is investigated. Three methacrylic acid-ethyl acrylate-coated fibrous dosage forms with φc = 0.025, 0.041, and 0.068 were prepared and tested. Upon administering to a pig, the dosage forms expanded to a normalized radial expansion of 0.5-0.6 in 5, 8, and 10 h, respectively. The expanded dosage forms resided in the stomach and fragmented after 11, 25, and 31 h. The fragments then passed into the intestines and dissolved in 2-3 h. Models suggest that upon contact with gastric fluid, a hydrostatic pressure develops in the fibers due to the inward diffusion of water. The hydrostatic pressure in turn induces a tensile stress in the coating and the dosage form expands. The tensile stress and the expansion rate are inversely proportional to φc. The expanded dosage form eventually fractures due to the loads applied by the contracting stomach walls. The post-expansion mechanical strength and the time to fracture increase steeply with φc. The models predict the experimental results reasonably well. Thus, by increasing φc, dosage form fracture is delayed and the gastric residence time prolonged.
Assuntos
Sistemas de Liberação de Medicamentos , Estômago , Animais , Cães , Suínos , Sistemas de Liberação de Medicamentos/métodos , Preparações de Ação Retardada , Formas de DosagemRESUMO
In this work, expandable fibrous dosage forms containing water-absorbing and fiber-strengthening excipients are investigated for prolonged delivery of sparingly-soluble drugs. The formulation comprised: sparingly-soluble ibuprofen drug; water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC) excipient; and strengthening methacrylic acid-ethyl acrylate excipient. Upon immersion in a dissolution fluid, the single fibers and all the dosage forms (fiber volume fractions, φ = 0.16, 0.39, and 0.56) expanded roughly at the same rate. The size of the dosage forms doubled in fifteen minutes, and they were converted into a highly viscous gel. The gel was stabilized by the strengthening excipient for over two days. Eighty percent of the drug was released from single fibers in less than an hour, and in thirty-eight hours from the dosage form with φ = 0.56. Theoretical models suggest that if φ is small, drug release is limited by the diffusion of drug molecules through the thin fibers, which is fast. If φ is large, however, drug release is limited by the diffusion of drug molecules through the thick, monolithic dosage form gel, which is slow. Between these extremes, the drug release time increases exponentially with φ.
Assuntos
Excipientes , Preparações Farmacêuticas , Preparações de Ação Retardada , Formas de Dosagem , Liberação Controlada de Fármacos , Derivados da Hipromelose , Metilcelulose , Solubilidade , ComprimidosRESUMO
Expandable, gastroretentive dosage forms are promising for precise control of drug concentration in blood. So far, however, short gastric residence times and safety considerations have limited their use. To mitigate such limitations, in this work expandable fibrous dosage forms were investigated for mechanical strength and gastric residence time in dogs. The fiber formulation comprised ibuprofen drug; water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC) excipient; fiber-strengthening, enteric methacrylic acid-ethyl acrylate excipient; and barium sulfate, a gastrointestinal contrast agent. The fibers were coated either with a hydrophilic sugar, or with a strengthening enteric excipient. Upon administration to a dog, in the stomach the dosage form with sugar-coated fibers expanded to 1.7 times its initial radius in 50-100 minutes, and disintegrated after 4.8 hours. The dosage form with the enteric-excipient-coated fibers, by contrast, expanded to 1.6 times the initial radius in 5 hours, and fractured after 31 hours due to cyclic loads applied by the contracting stomach walls. The fragments passed into the small intestine where they dissolved in less than 2-3 hours. Diametral compression tests and dynamic fatigue failure models show that the substantial increase in gastric residence time is due to strengthening of the fibers by the enteric-excipient coating. Because the enteric excipient is a rubbery semi-solid in the acidic gastric fluid and dissolves in the pH-neutral intestinal fluids, safety concerns should be minimal. Thus, expandable fibrous dosage forms can be readily designed for prolonged, safe gastric retention.
Assuntos
Preparações Farmacêuticas , Estômago , Animais , Cães , Excipientes , Intestino Delgado , Estômago/diagnóstico por imagemRESUMO
In part 1, we have investigated drug release by solid-solution single fibers comprising a sparingly water-soluble drug (ibuprofen) and a highly water-soluble dual excipient (low-molecular-weight hydroxypropyl methyl cellulose (HPMC) and polyoxyl stearate (POS)). In this part, fibrous dosage forms of the same formulation are prepared by 3D-micro-patterning, tested, and modeled. Upon immersion in a small volume of dissolution fluid, the dosage forms rapidly swelled and formed a low-viscosity medium, which subsequently dissolved. The dissolution time increased slightly with volume fraction of the fibers, φs, in the solid dosage form, but was less than 25 minutes even up to φs = 0.65. After dosage form dissolution, the fluid was supersaturated by a factor of two; the drug concentration then gradually decreased to solubility. The solubility was proportional to the concentration of POS, and was enhanced by a factor of six at φs = 0.65 (the most densely-packed dosage form). Theoretical models suggest that the dissolution fluid percolates the contiguous void space almost immediately, and the HPMC-POS fibers expand isotropically as water diffuses in. Because the void space remains contiguous in isotropic expansion, the dissolution fluid continues to percolate through and diffuse into the fibers. Thus, even the densely-packed dosage forms form a low-viscosity medium that deforms and dissolves rapidly. Consequently, the solid-solution fibrous dosage forms enable enhanced release rate, supersaturation, and solubility of sparingly-soluble drugs.
Assuntos
Preparações Farmacêuticas , Formas de Dosagem , Liberação Controlada de Fármacos , Excipientes , Derivados da Hipromelose , SolubilidadeRESUMO
In this work, the role of excipient molecular weight in drug release by close-packed, highly drug-loaded fibrous dosage forms is investigated. Three dosage forms with 87 wt% ibuprofen drug, and 13 wt% hydroxypropyl methylcellulose (HPMC) excipient of molecular weights 10, 26, and 86 kg/mol were prepared by wet 3D-patterning and drying. Upon immersion in a dissolution fluid, the dosage form with 10 kg/mol excipient fragmented and dissolved within 10 minutes. The dosage form with 26 kg/mol excipient fragmented slower, and dissolved in 60 minutes. The dosage form with 86 kg/mol excipient, however, did not fragment at all. Instead, a thick, highly viscous mass was formed that eroded slowly, in 500 minutes. Theoretical models suggest that the dissolution fluid rapidly percolates the inter-fiber void space, and a capillary pressure develops in the pores of the fibers. The fluid then diffuses into the fiber walls, and they transition to a viscous suspension. If the molecular weight of the excipient is small (~10 kg/mol), the viscosity is low and the suspension fragments and dissolves rapidly. If the molecular weight is moderate (~30 kg/mol), the fragmentation and dissolution rates are slower. If the molecular weight is large (~100 kg/mol), a thick, highly viscous mass is formed from which drug release is very slow. Thus, by appropriate choice of the molecular weight of the excipient, a wide range of drug release rates by close-packed, highly drug-loaded fibrous dosage forms can be realized.
Assuntos
Excipientes , Formas de Dosagem , Liberação Controlada de Fármacos , Derivados da Hipromelose , Peso Molecular , Solubilidade , ComprimidosRESUMO
Many drug therapies could be greatly improved by dosage forms that reside in the stomach for prolonged time and release the drug slowly. In this work, therefore, slow-release fibrous dosage forms that expand rapidly in the gastric fluid to prevent their passage into the intestines are investigated. The dosage forms consisted of acetaminophen drug and a high-molecular-weight hydroxypropyl methyl cellulose (HPMC) excipient. Upon immersion in a dissolution fluid, they transitioned to viscous, and expanded in proportion to the square-root of time and the reciprocal of fiber radius. The normalized axial expansion was up to 100 percent by fifteen minutes, fast enough to convert a swallowable, 10-mm diameter disk into a gastroretentive, 20-mm diameter viscous gel. The drug was released slowly, eighty percent in 2-8.4â¯hours. Theoretical models show that the fibrous dosage forms expand rapidly due to the fast diffusion of dissolution fluid into the thin fibers. The fibers then coalesce into a uniform viscous gel, and the diffusion length increases from the radius of the thin fibers to the half-thickness of the gelated dosage form. Consequently, drug diffusion out is slow, and the twin requirements, fast expansion and prolonged drug release, are simultaneously satisfied.
Assuntos
Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas , Preparações de Ação Retardada , Formas de Dosagem , Liberação Controlada de Fármacos , Excipientes , Derivados da Hipromelose , Solubilidade , ComprimidosRESUMO
Solid solutions of sparingly water-soluble drugs and highly water-soluble excipients are widely used for enhancing the drug delivery rate into the blood stream. The basic physico-chemical mechanisms, however, are not well understood. To delineate the mechanisms, therefore, in this work solid-solution fibers are immersed in a small volume of dissolution fluid and the drug concentration is monitored versus time. Two formulations are considered: ibuprofen drug and low-molecular-weight hydroxypropyl methyl cellulose (HPMC) excipient; and ibuprofen and HPMC and polyoxyl stearate (POS) excipients. The fibers dissolved in the dissolution fluid and the drug was released up to three orders of magnitude faster than by ibuprofen particles, yielding a maximum supersaturation in the fluid up to 6.5 in 10-15 minutes. Past the maximum, when the fiber was fully dissolved, the drug concentration gradually decreased to terminal solubility, up to a factor of 10 greater than that of pure ibuprofen. Models suggest that the drug release rate is proportional to the drug concentration at the fiber-fluid interface, which is enhanced due to both supersaturation and solubility-increase. The interface supersaturates because the drug-molecule release rate from the fast-eroding HPMC fibers is greater than the precipitation rate within; the solubility increases proportionally to the concentration of micelle-forming POS. Similarly, the dissolution fluid supersaturates, and due to the presence of POS in the solution the terminal solubility is increased. Thus the solid-solution fibers with dual, low-molecular-weight HPMC-POS excipient enhance the release rate, supersaturation, and solubility of sparingly-soluble drugs, and their delivery rate into the blood stream.
Assuntos
Derivados da Hipromelose/química , Soluções/química , Micelas , Peso Molecular , SolubilidadeRESUMO
At present, the most prevalent pharmaceutical dosage forms, the orally-delivered immediate-release tablets and capsules, are porous, granular solids. They disintegrate into their constituent particulates upon ingestion to release drug rapidly. The design, development, and manufacture of such granular solids, however, is inefficient due to difficulties associated with the unpredictable inter-particle interactions. Therefore, to achieve more predictable dosage form properties and processing, we have recently introduced melt-processed polymeric cellular dosage forms. The cellular forms disintegrated and released drug rapidly if the cells were predominantly interconnected. Preparation of interconnected cells, however, relies on the coalescence of gas bubbles in the melt, which is unpredictable. In the present work, therefore, new melt-processed fibrous dosage forms with contiguous void space are presented. The dosage forms are prepared by melt extrusion of the drug-excipient mixture followed by patterning the fibrous extrudate on a moving surface. It is demonstrated that the resulting fibrous structures are fully predictable by the extruder nozzle diameter and the motion of the surface. Furthermore, drug release experiments show that the disintegration time of the fibrous forms prepared in this work is of the order of that of the corresponding single fibers. The thin fibers of polyethylene glycol (excipient) and acetaminophen (drug) in turn disintegrate in a time proportional to the fiber radius and well within immediate-release specification. Finally, models of dosage form disintegration and drug release by single fibers and fibrous dosage forms are developed. It is found that drug release from fibrous forms is predictable by the physico-chemical properties of the excipient and such microstructural parameters as the fiber radius, the inter-fiber spacing, and the volume fraction of water-soluble excipient in the fibers.