The release profiles from the Test Capsules are depicted in Figure 4.The 90% confidence interval for comparing the maximum exposure, based on ln(Cmax), was outside the required 80% to 125% limits for oxycodone.OxyContin brand (oxycodone HCl controlled-release) Tablets, 40 mg strength (Lot W28A1, Purdue Pharma L.P.) were used as the commercial comparison.All of the above-described pharmacokinetic values can be readily determined by the skilled person using established in vivo clinical trail procedures such as those described below in Example 7.After breaking the vacuum, the pre-sieved network former (CAB) was added to the mixing bowl followed by the pre-sieved hydrophilic agent (HEC).The time to maximum plasma concentration may be adjusted by adjusting various components of the controlled release carrier system as taught herein.Based on these observations, a temperature of 280 C was selected for this study.
It is a primary object of the present invention to provide for improved pharmaceutical dosage forms and drug-delivery devices suitable for oral delivery of pharmacologically active agents, where such improved dosage forms and delivery devices are based upon the controlled release carrier systems described in the 382 Publication.For the microwave stress analysis, dosage forms are added to empty extraction bottles (if the dosage form is a solid tablet, it is crushed and then dropped into the bottle, if the dosage form is a liquid capsule, the capsule is cut to open the shell, and the liquid contents are squeezed from the capsule into the bottle).The weights successfully transfereed into each of five syringes was recorded.It is a further object of the present invention to provide an abuse-resistant oral pharmaceutical dosage form that includes a pharmacologically active agent and a controlled release carrier system.Example 7b: This next human clinical trial study was a single-center, three-way crossover, food effect, PK study to determine the rate and extent of absorption of 40 mg oxycodone base in abuse-resistant oral dosage forms when administered in a fasted state, after consumption of a low fat meal, and after consumption of a high fat meal.Previous dissolution studies with the dosage forms of the present invention have in fact given controlled release rate profiles well in excess of 100% release.In addition, exceptional stressing, such as the use of microwave and freeze-and-crush pretreatment of the dosage forms prior to extraction in the above-noted solvents can also be carried out.
Figure 4 shows the in vitro release performance of Test Capsules at 10, 20 and 40mg strength as described in Example 3a.Upon removal from the microwave, the appearance of the dosage form is recorded.The numerical results of the extraction panel study of this Example 4a, including the results discussed above and depicted in Figures 13 and 14, are reported below in Table 29.In a sixth step, hydroxyethyl cellulose (HEC) was inducted into the vessel using high shear dispersion during the addition and mixed to achieve a uniform dispersion with an anchor speed of 20-50 rpm, disperser speed of 700-3500 rpm and a rotor stator speed of 800-4500 rpm.Other suitable viscosity enhancing materials include stiffening agents such as clay compounds, including, talc, bentonite and kaolin, and metal oxides including silicon dioxide, zinc oxide, magnesium oxide, titanium oxide, and calcium oxide.
This volume of oil was selected since routine ingestion of a larger amount of oil would have a laxative effect and therefore was considered impractical.The label on the anti-static bag is checked to ensure that it is visible through the poly bag and the poly bag is sealed at its open end.After the administration of the 40 mg study dosage forms every 12 hours for five consecutive days, there was a significant increase in peak and overall systemic exposure to oxycodone, noroxycodone, and oxymorphone relative to exposure after the first dose.Accordingly, the oxycodone material was subjected to a jet milling process in order to micronize the solid material into a substantially homogenous particle size.The following information was considered in interpreting the outcome of each test.Both characteristics depend upon the viscosity and physical characteristics of a test formulation.Fix Erectile Dysfuction learn about treatment options for ED that results.ORAL PHARMACEUTICAL DOSAGE FORMS FIELD OF THE INVENTION The invention relates to oral pharmaceutical dosage forms and the use thereof.The controlled release carrier system is loaded with an active agent of interest, and will release the same over a period of time when in an aqueous environment, and in particular, an environment similar to that of the GI tract of a mammal.
The anti-static bag is placed into a poly bag with a layer of eight-unit, silica gel, printer, Natrasorb S Tyvek four-side seal bag desiccant separating the anti-static bag from the poly bag.Stimulants are frequently prescribed for treating narcolepsy, attention-deficit hyperactivity disorder (ADHD), and depression.These maximal and minimal plasma concentration ranges of course relate to the dose at the repeat dosage amount, wherein an effective dose is generally the effective AUC (at steady state).The active agent (oxycodone HCL) raw material was found to have a variety of different particle sizes and was further subject to agglomeration upon standing at ambient conditions.Two different commercial-scale manufacturing processes were developed for the dosage forms of the present invention.
For bulk formulation testing, 0.5 mL of the formulation is injected directly into the rheometer cup.The Cmax and Tmax values from this Example 7c study, based on mean oxycodone plasma concentration-time values, are presented below in Table 71.Forty-six subjects received all four doses of study dosage forms.Viscosity enhancing agents can be selected to have good hydrogen bonding capability, such as a bonding capability greater than or equal to one per molecule.The pH of the Vinegar, cola soft drink and saturated baking soda solution are determined using a pH meter and recorded prior to extraction studies.
The flow chart for Process Scheme 1 is depicted in Figure 1 A.This is necessary to maintain stabilized micronized opioid particle preparations.Preferably, the HVLCM is SAIB, the network former is CAB, the rheology modifier is 1PM, the hydrophilic agent is HEC, and the solvent is triacetin.
Plasma samples were analyzed for hydromorphone using a validated LC-MS-MS procedure.Accordingly, four Phase I In Vivo Abuse Resistance Evaluation studies were conducted to challenge abuse-resistant dosage forms of the present invention using physical and chemical manipulation in order to attempt to include dose dumping or immediate-release effect.
In particular, opioids, CNS-depressants, and stimulants are commonly abused.Therefore, data for the 40% ethanol treatment is only available for 18 subjects.The hydrophilic agent, which can include one or more suitable hydrophilic agent material, can be present in the formulations at from about 0.1 to about 10 percent by weight relative to the total weight of the formulation (wt%) used to produce the dosage forms of the present invention, preferably at from about 1 to about 8 wt%, and more preferably at from about 3 to about 6 wt%.