Patent Application
20080085304
The following examples are for purposes of illustration only and are not intended to limit the scope of the appended claims.
Some experiments were performed with albuterol sulfate, which has dosage, solubility and other physicochemical properties similar to opioids, such as oxymorphone and oxycodone.
Lots of TIMERx-N® sustained release delivery system were prepared according to the procedures related to those identified in U.S. Pat. Nos. 4,994,276, 5,128,143 and 5,554,387, incorporated herein by reference in their entirety.
Lots of xanthan gum (Jungbunzlauer, Perhoven, Austria or CP Kelco, Chicago, Ill.) were particle-size tested using a series of mesh sieves. These sieves included a #270 mesh sieve, which allowed particles smaller than 53 microns in diameter to pass through (fine particles). The weight fraction of xanthan gum particles passing through the sieves (i.e., fraction of fine xanthan gum) was determined. Batches with known fractions of fine xanthan gum particles were then prepared. TIMERx-N® was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum, calcium sulfate, and dextrose in a high speed mixer/granulator for 3 minutes. A slurry of hydrophobic polymer (ethylcellulose) was prepared by dissolving ethyl cellulose in ethyl alcohol. The slurry was added to the dry blended mixture and the material was subsequently granulated for 4 minutes while running the choppers/impeller. The granulation was then dried in a fluid bed dryer to a LOD (loss on drying) of less than 9% by weight (e.g., typical LOD was ˜3-5%). The granulation was then milled using a 1.0 mm (0.040″) screen. The ingredients of the sustained release excipient are set forth in Table 1:
Lots of TIMERx-M50A® sustained release delivery system were prepared according to the procedures related to those identified in U.S. Pat. No. 5,399,358, incorporated herein by reference in its entirety.
Xanthan gum batches with known fractions of fine particles were prepared according to Example 1. TIMERx-M50® was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum, calcium sulfate, and mannitol in a high speed mixer/granulator for 3 minutes. While running choppers/impellers, water was added to the dry blended mixture, and the mixture was granulated for another 3 minutes. The granulation was then dried in a fluid bed dryer to a loss on drying (LOD) of less than about 6% by weight. Typical LOD was between ˜3-5%. The granulation was then milled using a 0.065″ screen. The ingredients of the sustained release delivery system are set forth in Table 2.
A sustained release formulation was prepared by screening albuterol sulfate, ProSolv SMCC® 90 (Silicified Microcrystalline Cellulose, JRS Pharma LP, Patterson, N.Y.) and TIMERx-N®or TIMERx-M50A® separately through a #20 mesh sieve. The albuterol sulfate, ProSolv SMCC® 90 and either TIMERx-N® or TIMERx-M50A®, prepared according to Examples 1 and 2, respectively, were blended for 11 minutes in a Patterson-Kelley P/K Blendmaster V-Blender. Pruv™ (Sodium Stearyl Fumarate, NF, JRS Pharma LP, Patterson, N.Y.) was added to this mixture and the mixture was blended for five minutes. The blended granulation was compressed to 224.0 mg and ˜11 Kp hardness on a tablet press using 5/16″ round standard concave beveled edge tooling. The final tablet composition is listed in the Table 3.
Albuterol sulfate tablets with TIMERx-N® and TIMERx-M50A® sustained release delivery systems were prepared as described in Example 3. Dissolution profiles of tablets were evaluated using a USP Apparatus 2 dissolution tester in 900 mL of 50 mM potassium phosphate buffer (pH 4.5). The solution was stirred at 50 r.p.m. A series of samples of about 1.5 mL were withdrawn at predetermined intervals for a period of up to 14 hours.
Drug release for all tablets was monitored by RP-HPLC using a Waters Symmetry® C18 column (4.6×250 mm) (or equivalent) preceded by a Phenomenex® SecurityGuard™ C18 (4×3.0 mm) guard column. Monitoring wavelength was set to 226 nm. The mobile phase consisted of buffer: acetonitrile:methanol in 85:10:5 v/v ratios. The buffer consisted of 1 mL triethylamine and 1 mL trifluoroacetic acid in 1 L of H2O. The column temperature was 30° C. and the flow rate was set to 1.5 mL/min. To determine the percentage of drug released at each timepoint, the concentration of the sample taken at that timepoint was compared to the concentration of a standard solution. The standard solution was prepared by dissolving 45 mg of albuterol sulfate in 100 mL of 50 mM potassium phosphate buffer (pH 4.5) and then taking 5 mL of this solution and diluting it to 50 mL with more of 50 mM potassium phosphate buffer (pH 4.5).
Results of dissolution experiments with tablets made with alcohol/ethylcellulose-granulated TIMERx-N® comprising xanthan gum with different particle size distributions are shown in Table 4.
Tablets comprising 13.7% and 27.9% of fine xanthan gum in the ethanol/ethylcelluose-granulated TIMERx-N® released nearly the entire quantity of drug almost immediately. This is an example of undesired dose dumping. Tablets with 31.6% or more of fine xanthan gum dissolved in the expected sustained release manner. The data in Table 4 indicate that there appears to be no substantial difference in dissolution profiles of formulations containing between about 31.6% and about 88.8% of fine xanthan gum particles.
Results of dissolution experiments with tablets made with water-granulated TIMERx-M50A® comprising xanthan gum with different particle size distributions are shown in Table 5.
Tablets made by direct compression of water-granulated TIMERx-M50A® formulations comprising xanthan gum are not sensitive to xanthan gum particle size. The data in Table 5 indicate that there appears to be no substantial difference between the dissolution profiles of tablets made with xanthan gum having particle size of less than 180 microns and less than 75 microns when xanthan gum is granulated with water in the process of making the formulation.
Table 6 shows dissolution profiles of tablets made by direct compression and granulation of ethanol/ethylcellulose-granulated sustained release formulations with different fractions of #270 (fine) mesh xanthan gum particles.
Comparison of dissolution profiles of tablets comprising TIMERx-N® that were manufactured either using direct compression or wet granulation in the tableting step, shows that robustness of tablets appears to be sensitive to xanthan gun particle size when the tablets are manufactured by direct compression, but not when they are manufactured by wet granulation. Tablets with ethanol/ethylcellulose-granulated TIMERx-N® with 27.9% of fine particles had desired dissolution profiles when tableted using wet granulation, but not when tableted using direct compression. Direct compression of ethanol/ethylcellulose-granulated formulations produced tablets with desired dissolution profiles when the fraction of fine xanthan gum was more than about 30%.
Tablets of TIMERx-N® formulations of albuterol sulfate were prepared as described in Example 3. Dissolution profiles of each formulation were measured as described in Example 4. A medium of 40% ethanol and 60% 0.1 M HCl was used as a model of dissolution in the presence of alcohol. 0.1 M HCl was chosen to mimic the biological environment of upper GI tract/stomach area, where the sustained release formulation first begins to release the drug.
Dissolution experiments were performed using a USP II Type dissolution apparatus according to methods described above. Results of dissolution experiments with tablets made with alcohol/ethylcellulose-granulated TIMERx-N® comprising xanthan gum with different particle size distributions are shown in Table 7.
Tablets comprising 28% of fine xanthan gum in the ethanol/ethylcelluose-granulated TIMERx-N® released nearly the entire quantity of drug almost immediately. This is an example of undesired dose dumping. Tablets with 35% or more of fine xanthan gum dissolve in the expected sustained release manner. The data in Table 7 indicate that there appears to be no substantial difference in dissolution profiles of formulations containing between about 35% and about 86% of fine xanthan gum particles, although the formulation containing about 86% of fine xanthan gum particles dissolved slightly slower in 40% ethanol solution than in a standard buffer.
Therefore, formulations comprising about 30% or more of fine xanthan gum, exhibit robust dissolution properties, and dissolve in a sustained release manner in the presence and absence of beverage-strength ethanol.
A controlled release delivery system was prepared by dry blending xanthan gum, locust bean gum, calcium sulfate dihydrate, and dextrose in a high speed mixed/granulator for a few minutes. A slurry was prepared by mixing ethyl cellulose with alcohol. While running choppers/impellers, the slurry was added to the dry blended mixture, and granulated for a few minutes. The granulation was then dried to a LOD (loss on drying) of less than about 10% by weight. The granulation was then milled using a screen. The relative quantities of the ingredients used to prepare the sustained release delivery system are listed in Table 8A.
Tablets comprising 40 mg of oxymorphone hydrochloride were prepared using the controlled release delivery system shown in Table 8A. The quantities of ingredients per tablet are listed in Table 8B.
Tablets of TIMERx-N® sustained release formulations with 40 mg of oxymorphone were tested for abuse potential in an intravenous route of administration. A person, such as a drug addict, trying to abuse the formulation, may attempt to extract the opioid from the tablets and inject themselves with the resulting solution.
Tablets of TIMERx-N® sustained release formulations with 40 mg of oxymorphone were prepared according to procedures in Example 6 and ground into powder. In the water extraction test, the resulting powder was dispersed into 30 mL of water and stirred for 5 seconds. In the 95% ethanol/water extraction test, the resulting powder was dispersed into 15 mL of 95% ethanol, stirred for 5 seconds, and then diluted with an additional 15 mL of water. In the 95% ethanol extraction test, the resulting powder was dispersed into 30 mL of 95% ethanol and stirred for 5 seconds. In each test, the resulting solution was allowed to set for 15 minutes before being filtered through a paper filter. Oxymorphone recovery from the filtered solutions was measured using HPLC at 40° C., using a Zorbax® XDB-C18 column and a UV detector set at 230 nm. Recovery of oxymorphone from each test is shown in Table 9.
When sustained release tablets comprising 40 mg of oxymorphone, formulated with TIMERx-N® made with xanthan gum in which at least 30% of particles can pass through a #270 mesh sieve, were powdered and extracted with water, approximately 3-4% of oxymorphone was released into water after 15 minutes. To mimic abuse by dropping a tablet into 95% ethanol and then diluting it to an ingestible concentration, powdered tablets were first suspended in 95% ethanol for 5 seconds, followed by dilution with water to provide a 47.5% ethanol solution. In this experiment, approximately 1-15% of oxymorphone was released into the water/ethanol solution after 15 minutes. The powdered sustained release 40 mg oxymorphone tablets formulated with TIMERx-N® with xanthan gum of which at least 30% of the particles can pass through a #270 mesh sieve, therefore, resist extraction in more than one potential abuse scenario.
Sustained release 40 mg oxymorphone tablets were prepared as described in Example 6. Dissolution tests were performed on sets of 12 tablets in 500 mL of 0.1N HCl and ethanol/0.1N HCl solutions at 4%, 20%, and 40% ethanol concentrations. Oxymorphone release was determined by HPLC as described above.
Tablets remained intact throughout the dissolution tests in all media. Mean concentrations of oxymorphone released are shown in Table 10A. Similarity factors (f2) for the ethanol dissolution media against the 0.1N HCl medium were calculated using standard methods and the results indicate that the drug release rate is inversely correlated with the amount of ethanol in the dissolution medium (Table 10B). An increase in ethanol content of the dissolution medium moderately decreased the drug release rate.
Results of dissolution experiments are summarized in Table 10A.
The presence of up to 40% ethanol did not significantly affect the dissolution profile of sustained release 40 mg oxymorphone tablets. The presence of 4% ethanol had an insignificant effect on the dissolution profile of 40 mg sustained release oxymorphone tablets compared to their dissolution profile in the absence of ethanol. Oxymorphone release was inversely correlated with the amount of ethanol in the dissolution medium. Presence of 20% and 40% ethanol in the dissolution medium slowed down the release of oxymorphone, which was still released in a controlled manner. No dose dumping was observed at concentrations of ethanol between 0% and 40%. Therefore, tablets with sustained release formulations described herein release oxymorphone in a controlled manner in the presence of up to at least 40% ethanol.
Similarity factors for ethanol-containing media relative to 0.1N HCl medium (0% ethanol) were 97, 60 and 45 for the 4%, 20% and 40% ethanol solutions, respectively. Thus, oxymorphone tablets resist beverage strength concentrations of ethanol and do not dose dump in the presence of at least up to 40% ethanol.
Healthy volunteers were used in a study to assess the pharmacokinetics of oxymorphone 40 mg sustained release tablets when co-administered with 240 mL of 40%, 20%, 4%, and 0% (water) ethanol.
The study design was a randomized, open-label, single-dose, four-period crossover in 28 subjects. To block the opioid effects of oxymorphone, naltrexone HCl (50 mg) was administered approximately 12 and 2 hours prior to each oxymorphone administration, and again at 12 hours after administration. Subjects were fasted overnight for at least 8 hours prior to dosing. Water was allowed ad lib except from 1 hour before dosing until 1 hour after dosing. A standardized meal was served 4 hours and 10 hours after dosing.
Oxymorphone 40 mg sustained release tablets were administered on four separate occasions with 240 mL of: A) 40% ethanol, B) 20% ethanol, C) 4% ethanol, or D) 0% ethanol. Serial blood samples were obtained from 0 to 48 hours after dosing. Plasma samples were assayed for oxymorphone. Pharmacokinetic parameters for oxymorphone were determined using non-compartmental methods for data evaluation. Point estimates and 90% confidence intervals (CIs) for natural logarithmic transformed Cmax, AUC0-t, and AUC0-inf were calculated using Least Squares Means (LSMeans). Any treatment in which a subject vomited during the dosing interval (0-12 hours) was excluded from the primary pharmacokinetic analysis.
Thirty subjects were enrolled in the study. Twenty-five subjects completed the study, meaning these subjects received all four treatments. Subjects who vomited within the dosing interval (0-12 hours) were to have that treatment excluded from the pharmacokinetic analysis. There were 10 subjects who vomited between 0-12 hours on treatment A (40% ethanol) and 5 subjects who vomited between 0-12 hours on treatment B (20%) ethanol. There were no subjects who vomited on treatments C (4% ethanol) or D (0% ethanol). Mean plasma concentration-time data for each treatment, excluding subject data from a treatment if the subject vomited, are shown in Table 11.
Statistical analyses of the pharmacokinetic parameters are presented in Table 12.
αn = 13
bn = 24
Geometric mean ratios (GMR) and 90% CI for those treatments in which subjects completed the study without vomiting between 0-12 hours are shown in Table 13.
The mean plasma concentration-time data in Table 11 show that the 40% and 20% ethanol treatments produce higher plasma concentrations during the first 4 to 6 hours compared to the 0% ethanol treatment. The 4% ethanol treatment mean plasma concentrations were similar to those for the 0% ethanol treatment. All data were comparable from 16 to 48 hours after dosing. Secondary peaks were observed at 5 hours for the 4% and 0% ethanol treatments and 12 hours for all four treatments. Although the 40% ethanol treatment mean plasma concentration was higher than 0%, 4%, or 20% from 0.5 to 6 hours, the concentration then declined and was lower than the other three treatments at 8 to 12 hours. Cmax was the only pharmacokinetic parameter that appeared to be directly related to the ethanol treatment (Table 12). From the ratios shown in Table 13, it can be seen that the increases in Cmax were 70%, 31%, and 7% for the 40% ethanol, 20% ethanol and 4% ethanol treatments, respectively, compared to the 0% ethanol treatment. Changes in AUC0-t and AUC0-inf ranged from 1% to 13% for the ethanol treatments compared to 0% ethanol (Table 13). Other than Cmax, no significant differences for the pharmacokinetic parameters were observed among various treatments.
Analysis of all subjects regardless of whether they vomited is presented in Tables 14 and 15. Mean plasma concentration-time data for each treatment, without any exclusions for vomiting, are shown in Table 14.
Mean plasma concentration-time profiles without excluding treatments (n=25) in which subjects vomited (Table 14), showed the 40% ethanol treatment with a secondary peak at 5 hours, which was not clearly evident in Table 11, where only 15 subjects were represented. The 20% ethanol treatment (n=25) appeared to be similar to that of Table 11, where there were 20 subjects. The 4% and 0% ethanol treatments represented the same sample of subjects as those in Table 11. As previously indicated in Table 12, Cmax was the only pharmacokinetic parameter that appeared to be directly related to the ethanol treatment (Table 15).
an = 22
bn = 23
GMR data shown in Table 16 indicate that increases in Cmax were 62%, 15%, and 8% for the 40% ethanol, 20% ethanol and 4% ethanol treatments, respectively, as compared to the 0% ethanol treatment. Changes in AUC0-t, and AUC0-inf ranged from −10% to 7% for the ethanol treatments as compared to 0% ethanol (Table 16). The 40% and 20% Cmax, AUC0-1, and AUC0-inf increases were lower when subjects who vomited were included.
A study was performed in healthy volunteers to assess the effect of food on the bioavailability of sustained release 40 mg oxymorphone tablets and oxymorphone immediate release tablets (4×10 mg). The study design was a randomized, open-label, single-dose, four-period crossover in 28 subjects. The 40 mg oxymorphone sustained release tablet and 4×10 mg oxymorphone immediate release tablets were evaluated under fed and fasted conditions. To block the opioid effects of oxymorphone, naltrexone HCl (50 mg) was administered approximately 12 hours prior to each oxymorphone administration. Subjects were fasted overnight for at least 8 hours prior to dosing. For the fed treatment subjects were served a high-fat breakfast and were dosed 10 minutes after completion of the breakfast. Each dose was administered with 240 mL of water. Subjects were not permitted any other food until 4 hours after dosing. Serial blood samples were obtained from 0 to 72 hours after dosing. Plasma samples were assayed for oxymorphone. Pharmacokinetic parameters for oxymorphone were determined using non-compartmental methods. Point estimates and 90% CIs for natural logarithmic transformed Cmax, AUC0-t, and AUC0-inf were calculated using LSMeans.
Twenty-five subjects completed the study. The mean plasma concentration-time data for the fasted and fed treatments for the sustained release tablet are shown in Table 17.
As shown in Table 17 the fed treatment produced higher plasma oxymorphone concentrations during the first 8 hours compared to the fasted treatment. The mean plasma concentrations for both treatments were similar from 10 to 48 hours after dosing. Secondary peaks were observed at 5 hours for the fasted treatment and at 12 hours both treatments. The mean plasma oxymorphone concentration-time data or the fasted and fed treatments for the immediate release tablets are shown in Table 18. The fed treatment produced higher plasma concentrations during the first 10 hours compared to the fasted treatment. The mean plasma concentrations for both treatments were similar from 12 to 48 hours after dosing. Secondary peaks were seen at 12 hours for the fasted and fed treatments.
Mean plasma oxymorphone concentration time profiles for the fed and fasted treatments for the immediate release oxymorphone tablets (4×10 mg) are shown in Table 18.
The fed treatment with 4×10 mg immediate release oxymorphone tablets produced higher plasma oxymorphone concentrations during the first 10 hours compared to the fasted treatment. The mean plasma oxymorphone concentrations for both treatments were similar from 12 to 48 hours after dosing. Secondary peaks were observed at 12 hours for the fasted treatment and fed treatments. Cmax was increased in the presence of food for both the sustained release and the immediate release tablets and AUC was increased by food for the immediate release tablets (Table 19). From the GMR data (Table 20) it can be seen that food increased Cmax by 51% and 38% for the sustained release and immediate release tablets, respectively, when compared to administration under fasted conditions. Food increased AUC0-t and AUC0-inf by 43% and 38%, respectively for the immediate release tablets. For the sustained release tablet administered with food, the AUC0-t and AUC0-inf increases were less than 10% and the 90% CIs were within 80-125%.
From the GMR data (Table 20) it can be seen that food increased Cmax by 51% and 38% for the sustained release and immediate release tablets, respectively, when compared to administration under fasted conditions. Food increased AUC0-t and AUC0-inf by 43% and 38%, respectively for the immediate release tablets. For the sustained release tablet, the AUC0-t and AUC-inf increases with food were small and the 90% CIs were within 80-125%.
The in vitro study (Example 8) showed that 40% ethanol did not increase the dissolution rate of the oxymorphone sustained release 40 mg tablet. These data indicate that the formulation drug release matrix is not compromised by beverage-strength ethanol concentrations and the premature release of oxymorphone in vivo when exposed to ethanol at concentrations up to 40% does not occur. However, the data from the human ethanol study demonstrated that co-administration of 240 mL of 40% ethanol, and to a lesser extent 20% ethanol, increased the Cmax of oxymorphone from the 40 mg sustained release tablet while having no demonstrable effect on the AUC (Tables 12 and 13). The in vitro and in vivo results suggest that beverage-strength ethanol does not directly effect the integrity of formulation, but may cause other effect(s), that can lead to an apparent increased rate of absorption of oxymorphone.
Interestingly, an increased rate of absorption of oxymorphone is also observed when oxymorphone 40 mg sustained release tablets are administered after a high-fat meal (Tables 19 and 20). The magnitude of the increase and the plasma concentration-time course are similar when oxymorphone tablets formulated with TIMERx-N® are administered after a high-fat meal or with ethanol (see Tables 11 and 16). This observation suggests that there may be a common mechanism between food and ethanol leading to the increase in Cmax. The pharmacokinetic parameters measured following dosing of oxymorphone immediate release tablets and oral solutions were also affected when taken after a high-fat meal (Tables 19 and 20). In addition to an increase in Cmax, the AUC for the immediate release tablets also increased, unlike the results for the sustained release tablets, where AUC did not change appreciably after ethanol or food. These differences suggest that the sustained release tablets are not releasing oxymorphone at an accelerated rate in the presence of ethanol, but that it is only the level of oxymorphone dissolved in the gastrointestinal tract that is affected by the food or ethanol.
The in vitro results indicate no oxymorphone sustained release formulation-ethanol interaction. The results from the bioavailability study demonstrated that there is a pharmacokinetic interaction when 40 mg oxymorphone sustained release tablet is consumed with 240 mL of 40% ethanol, which represents an excessive intake of ethanol, with resultant increases in peak plasma concentrations similar to those observed when oxymorphone sustained release tablets are taken after a standardized high-fat meal. The underlying mechanism of this phenomenon is not clear at present.
Based on evaluation of the in vitro and earlier in vivo data, the increases in Cmax observed are not believed to be caused by early release of oxymorphone owing to disintegration of the sustained release delivery system (i.e., dose dumping), but instead by an apparent increased rate of absorption, which is independent of the formulation.
Similar results are expected to be obtained with other drugs, because the properties of the sustained release system affect the dissolution properties of the formulation to a significantly larger extent than the nature of the drug in the formulation. Ethanol dissolution testing is contemplated to become a standard procedure in the development of new sustained release products.
The patents, patent applications, and publications cited herein are incorporated by reference herein in their entirety.
Various modifications of the invention, in addition to those described herein, will be apparent to one skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
