PHENYLEPHRINE RESINATE PARTICLES AND USE THEREOF IN PHARMACEUTICAL FORMULATIONS

Abstract

Phenylephrine particles suitable for solid, semi solid or liquid dosage forms are disclosed.

Claims

1-13. (canceled)

14. A pharmaceutical formulation comprising two or more extended release particles comprising: a drug-resin complex comprising phenylephrine and a cation polystyrene sulfonate, wherein at least 90% of the cation polystyrene sulfonate comprises particle sizes of about 74 μm to about 177 μm prior to being combined with the phenylephrine; and a coating to coat the drug-resin complex to a coating level, wherein the coating level is the same for each of the two or more extended release particles at an amount of from 30% to 45% by weight of the drug-resin complex, wherein the coating consists of cellulose acetate and hydroxypropylcellulose, and wherein the coating consists of from 67% to 83% by weight cellulose acetate, wherein the two or more extended release particles exhibit bioavailability for at least about 8 hours upon administration, wherein a serum concentration of the two or more extended release particles exhibits intersubject variability within the range depicted in FIG. 2 upon administration to two or more subjects, and wherein the serum concentration of the two or more extended release particles exhibit a second peak at about 12 hours after administration in said subjects.

15. The pharmaceutical formulation of claim 14, wherein the cation polystyrene sulfonate is selected from the group consisting of sodium, copper, zinc, iron, calcium, strontium, magnesium and lithium.

16. The pharmaceutical formulation of claim 15, wherein the cation polystyrene sulfonate is sodium.

17. The pharmaceutical formulation of claim 14, further comprising an immediate release form of phenylephrine.

18. The pharmaceutical formulation of claim 14, wherein the amount of the coating as compared to the drug-resin complex is 35% by weight.

19. The pharmaceutical formulation of claim 14, wherein the amount of the coating as compared to the drug-resin complex is 40% by weight.

20. The pharmaceutical formulation of claim 14, wherein said two or more extended release particles exhibit bioavailability for at least about 12 hours upon administration.

21. The pharmaceutical formulation of claim 14, further comprising a therapeutic agent selected from the group consisting of antihistamines, decongestants, analgesics, anti-inflammatories, anti-pyretics, cough suppressants, and expectorants.

22. The pharmaceutical formulation of claim 21, wherein the therapeutic agent is acetaminophen.

23. The pharmaceutical formulation of claim 21, wherein the therapeutic agent is selected from the group consisting of bromopheniramine, chlorcyclizine, dexbrompheniramine, bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine, pripolidine, ephedrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine, naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine, clemastine, acrivastine, promethazine, oxomemazine, mequitazine, buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide, xylomeazoline, loratadine, desloratadine, and cetirizine; isomers thereof, and pharmaceutically acceptable salts and esters thereof.

24. The pharmaceutical formulation of claim 21, wherein the therapeutic agent is selected from the group consisting of ibuprofen, naproxen, ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, celecoxib, acetaminophen, acetyl salicylic acid, indomethacin, diclofenac, sulindac, tolmetin, mefanamic acid, meclofenamic acid, flufenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof, and pharmaceutically acceptable salts and prodrugs thereof.

25. The pharmaceutical formulation of claim 21, wherein the therapeutic agent is selected from the group consisting of diphenhydramine, dextromethorphan, noscapine, clophedianol, menthol, benzonatate, ethylmorphone, codeine, acetylcysteine, carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, and guaifenesin; isomers thereof, and pharmaceutically acceptable salts and prodrugs thereof.

26. A pharmaceutical formulation comprising an extended release particle comprising: a drug-resin complex comprising phenylephrine and a cation polystyrene sulfonate, wherein at least 90% of the cation polystyrene sulfonate comprises particle sizes of about 74 μm to about 177 μm prior to being combined with the phenylephrine; and a coating to coat the drug-resin complex to a uniform coating level, wherein the coating is in an amount of 35% by weight of the drug-resin complex, wherein the coating consists of 75% cellulose acetate and 25% hydroxypropylcellulose by weight, wherein the extended release particle exhibits bioavailability for at least about 8 hours upon administration, wherein a serum concentration of the extended release particle exhibits intersubject variability within the range depicted in FIG. 2 upon administration to two or more subjects, and wherein the serum concentration of the extended release particle exhibit a second peak at about 12 hours after administration in said subjects.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0038] FIG. 1 shows the mean plasma concentration profile of phenylephrine upon administration of coated extended release (ER) phenylephrine resinate particles containing 20 mg phenylephrine. Referring to FIG. 1, the y axis represents the concentration of free phenylephrine in plasma in picograms (pg) per milliliter (mL). The x axis represents time in hours. FIG. 1 shows that the average concentration of phenylephrine reached a peak (Cmax) at about 2 hours. FIG. 1 also shows a secondary peak at about 12 hours.

[0039] FIG. 2 shows the individual plasma concentration profiles of phenylephrine upon administration of coated ER phenylephrine resinate particles containing 20 mg phenylephrine. Referring to FIG. 2, the intersubject variability is good for modified release phenylephrine. The range of Cmax occurred from about 1 hour to about 4.5 hours. The secondary peak at about 12 hours was observed for all subjects.

[0040] FIG. 3 shows the mean plasma concentration profile of phenylephrine upon administration of coated ER phenylephrine HCl particles containing 20 mg phenylephrine. Referring to FIG. 3, the dashed line is the profile from FIG. 1 for comparison purposes. A slightly higher Cmax with the phenylephrine resinate particles was observed. A secondary peak at about 12 hours is observed in both profiles. This may be the result of less phenylephrine being metabolized presystemically by the gut wall as a result of the particles quick movement down the GI tract. Release of phenylephrine in the colon would result in higher absorption at a later time.

[0041] FIG. 4 shows the individual plasma concentration profiles of phenylephrine upon administration of coated ER phenylephrine HCl particles containing 20 mg phenylephrine.

[0042] FIG. 5 shows the mean plasma concentration profile of phenylephrine upon administration of coated ER phenylephrine resinate particles containing 15 mg phenylephrine and liquid IR phenylephrine HCl containing 5 mg phenylephrine (the “ER-IR blend”). Referring to FIG. 5, the unbroken line represents the ER-IR blend. Again, the curve for this treatment is consistent with what was seen with the resinate and the HCl formulations. For the ER-IR blend, there are two peaks within the first 2 hours; one mainly from the IR dose and the other from the accumulation of the IR and ER doses. The Cmax was reached faster and maintained for a longer period of time. An ER-IR blend thus appears beneficial in terms of onset of efficacy.

[0043] FIG. 6 shows the individual plasma concentration profiles of phenylephrine upon administration of coated ER phenylephrine resinate particles containing 15 mg phenylephrine and liquid IR phenylephrine HCl containing 5 mg phenylephrine.

[0044] FIG. 7 shows the mean plasma concentration profile of phenylephrine upon administration of liquid IR phenylephrine HCl containing 20 mg phenylephrine. Referring to FIG. 7, the unbroken line represents the profile for the currently marketed IR liquid product and the dashed line is the profile from FIG. 5 for comparison. The Cmax of the ER-IR blend is lower than the Cmax of the IR form.

[0045] FIG. 8 shows the individual plasma concentration profiles of phenylephrine upon administration of liquid IR phenylephrine HCl containing 20 mg phenylephrine.

[0046] FIG. 9 shows the mean plasma concentration profile of phenylephrine upon administration of coated ER phenylephrine resinate particles containing 22.5 mg phenylephrine and liquid IR phenylephrine HCl containing 7.5 mg phenylephrine (the “ER-IR blend”) and compares to liquid IR phenylephrine HCl containing 20 mg phenylephrine.

[0047] FIGS. 10A and 10B compare the mean plasma concentration profile of phenylephrine (1) upon administration of coated ER phenylephrine resinate particles containing 15 mg phenylephrine and liquid IR phenylephrine HCl containing 5 mg phenylephrine (FIG. 10A) and (2) upon administration of coated ER phenylephrine resinate particles containing 22.5 mg phenylephrine and liquid IR phenylephrine HCl containing 7.5 mg phenylephrine (FIG. 10B) with (3) liquid IR phenylephrine HCl containing 20 mg phenylephrine.

[0048] FIG. 11 compares the mean plasma concentration profiles of phenylephrine upon administration of (1) coated ER phenylephrine resinate particles containing 15 mg phenylephrine and liquid IR phenylephrine HCl containing 5 mg phenylephrine with a (2) combination of (a) coated ER phenylephrine resinate particles containing 15 mg phenylephrine, (b) liquid IR phenylephrine HCl containing 5 mg phenylephrine and (c) 1300 mg ER acetaminophen.

DETAILED DESCRIPTION OF THE INVENTION

[0049] It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not as limiting the remainder of the disclosure in any way whatsoever.

[0050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. As used herein, all percentages are by weight unless otherwise specified. In addition, all ranges set forth herein are meant to include any combinations of values between the two endpoints, inclusively.

Definitions

[0051] As used herein a pharmaceutically acceptable salt of phenylephrine includes, but is not limited to, phenylephrine hydrochloride, phenylephrine bitartrate, phenylephrine tannate, etc. In one preferred embodiment, the pharmaceutically acceptable salt of phenylephrine is phenylephrine hydrochloride.

[0052] “AUC” as used herein means, for any given drug, the “area under the concentration-time curve” from dosing or activation of the drug to a time point, calculated by the trapezoidal rule. AUC is a parameter showing the cumulative plasma concentration of a drug over time, and is an indicator of the total amount and availability of a drug in the plasma.

[0053] “Cmax” as used herein means the maximum (or peak) concentration that a drug achieves in tested area after the drug has been administrated and prior to the administration of a second dose.

[0054] As used herein, “crystalline form” shall mean the non-amorphous form of the active ingredient such that it displays crystal like properties including, but not limited to, the ability to diffract visible light. Crystalline may also be used to describe an active ingredient in its pure form, i.e., e.g., without the addition of other excipients thereto.

[0055] By “delayed release,” it is meant that, after administration, there is at least one period of time when an active ingredient is not being released from the dosage form, i.e., the release of the active ingredient(s) occurs at a time other than immediately following oral administration.

[0056] As used herein, “dissolution medium” shall mean any suitable liquid environment in which the suspension dosage form of the present invention can be dissolved, such as, for example, the in vitro dissolution media used for testing of the product, or gastro-intestinal fluids. Suitable in vitro dissolution media used for testing the dissolution of the active ingredient or ingredients from the suspension dosage form of the present invention include those described in the United States Pharmacopeia.

[0057] A “dosage”, “dosage form” or “dose” as used herein means the amount of a pharmaceutical composition comprising therapeutically active agent(s) administered at a time. “Dosage”, “dosage form” or “dose” includes administration of one or more units of pharmaceutical composition administered at the same time. In one embodiment, the dosage form is a tablet. In one embodiment the dosage form is a multilayer tablet. In the embodiment comprising a multilayer tablet, one layer may comprise an immediate release portion and another layer may comprise an extended release portion. In the embodiment comprising a multilayer tablet, one layer may comprise the phenylephrine resinate particles, and another layer may comprise an immediate release form of phenylephrine and/or a second active ingredient. In one embodiment the dosage form comprising phenylephrine resinate particles is a liquid filled soft-gel.

[0058] As used herein “drug-resin complex” shall mean the bound form of an active ingredient, including but not limited to the pharmaceutical active ingredients, and an ion exchange resin. The drug-resin complex is also referred to in the art as a “resinate.” An ion exchange resin that may be used in accordance with the invention is Amberlite™ IRP 69, The Dow Chemical Company, an insoluble, strongly acidic, sodium form cationic exchange resin derived from sulfonated copolymer of styrene and divinylbenzene. The mobile, or exchangeable cation is sodium, which can be exchanged for, or replaced by, many cationic (basic) species, including, e.g., copper, zinc, iron, calcium, strontium, magnesium and lithium. Adsorption of drug onto ion exchange resin particles to form the drug/resin complex is a well known technique as shown in U.S. Pat. Nos. 2,990,332 and 4,221,778. In general the drug is mixed with an aqueous suspension of the resin, and the complex is then washed and dried. Adsorption of drug onto the resin may be detected by measuring a change in the pH of the reaction medium, or by measuring a change in concentration of sodium or drug. The drug/resin complex formed can be collected and washed with ethanol and/or water to insure removal of any unbound drug. The complexes are usually air-dried in trays at room or elevated temperature. The drug/resin complex has a ratio of phenylephrine to resin of about 0.25:1 to about 0.65:1, preferably about 0.30:1 to about 0.55:1, preferably about 0.35:1 to about 0.45:1.

[0059] “Enteric” shall mean being able to be dissolved at a pH of greater than about 5.0 or greater than about 5.5 or greater than about 6.0 or that which is found in the intestine.

[0060] By “extended release,” it is meant that, after administration, an active ingredient is released from the dosage form in a substantially continuous, regulated manner, and the time for complete release, i.e., depletion, of the active ingredient from the dosage form is longer than that associated with an immediate release dosage form of the same. Types of extended release include controlled, sustained, prolonged, zero-order, first-order, pulsatile, and the like.

[0061] As used herein, “immediate release” means that the dissolution characteristics of at least one active ingredient meet USP specifications for immediate release tablets containing that active ingredient. An active ingredient having an immediate release property may be dissolved in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution of the active ingredient.

[0062] “Liquid dosage forms” may nonexclusively include suspensions or elixirs, wherein one or more of the active ingredients is dissolved, partially dissolved or in an undissolved or suspended state.

[0063] As used herein, “modified release” shall apply to the altered release or dissolution of an active ingredient in a dissolution medium, such as gastrointestinal fluids. Types of modified release include: 1) extended release; or 2) delayed release. In general, modified release dosage forms are formulated to make the active ingredient(s) available over an extended period of time after ingestion, which thereby allows for a reduction in dosing frequency compared to the dosing of the same active ingredient(s) in a conventional dosage form. Modified release dosage forms also permit the use of active ingredient combinations wherein the duration of one active ingredient may differ from the duration of another active ingredient.

[0064] As used herein, “pharmacodynamics” or “PD” is the study of the relationship between drug concentration at the site of action and the resulting effect.

[0065] As used herein, “pharmacokinetics” or “PK” is the study of the time course of drug absorption, distribution, metabolism and excretion.

[0066] As used herein, the term “phenylephrine” means benzynemethanol, 3-hydroxy-a-[(methylamino)methyl], and includes, but is not limited to pharmaceutically acceptable salts, esters, isomers or derivatives thereof.

[0067] As used herein, a drug “release rate” refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hr). Drug release rates are calculated under in vitro dosage form dissolution testing conditions known in the art. As used herein, a drug release rate obtained at a specified time “following administration” refers to the in vitro drug release rate obtained at the specified time following commencement of an appropriate dissolution test, e.g., those set forth in USP 24 (United States Pharmacopeia 24, United States Pharmacopeia Convention, Inc., Rockville, Md.).

[0068] “Semipermeable,” as used herein, shall mean that water can pass through, and other molecules, including salts and the active ingredients described herein, are allowed to slowly diffuse through such a membrane when the membrane is in contact with an appropriate dissolution medium, e.g., gastro-intestinal fluids or in-vitro dissolution media.

[0069] “Semi-solid dosage forms” shall mean dosage forms which are highly viscous and share some of the properties of liquids, including but not limited to (1) having the ability to substantially conform to something that applies pressure to it and causes its shape to deform; and (2) lacking the ability to flow as easily as a liquid. Semi-solid dosage forms also share some of the properties of solids, including but not limited to having a higher density and a defined shape. Semi-solids may nonexclusively include gels, chewy dosage forms, pectin based chewy forms, confectionery chewy forms, moldable gelatin type of forms.

[0070] “Solid dosage forms” shall mean dosage forms which are substantially solid at room temperature and have a density of at least about 0.5 g/cc. Solid dosage forms may non exclusively include, agglomerated tablets, capsule-like medicaments, powder or granule filled capsules, powder or granule filled sachets, compressed tablets, coated tablets, chewable dosage forms, and fast-dissolving dosage forms.

[0071] As used herein, “substantially coated” with regard to particles shall mean that less than about 20%, e.g., less than about 15%, or less than about 1.0% of the surface area of the particle is exposed, e.g., not covered, with a desired coating. As used herein, the term “substantially covers” or “substantially continuous” when used to describe a coating means that the coating is generally continuous and generally covers the entire surface of the core or underlying layer, so that little to none of the active ingredient or underlying layer is exposed. The coatings which are applied to the particles can be layered wherein each layer is prepared in an aqueous (water based) or organic solvent system and added in succession until the desired coating level is achieved.

[0072] “Therapeutic effect,” as used herein, shall mean any effect or action of an active ingredient intended to diagnose, treat, cure, mitigate, or prevent disease, or affect the structure or any function of the body.

[0073] Specific embodiments of the present invention are illustrated by way of the following examples. This invention is not confined to the specific limitations set forth in these examples.

Examples

[0074] Phenylephrine extended release particles were developed in order to formulate into liquid and solid dosage forms. The phenylephrine extended release particles can be used to match duration with other actives (particularly pain actives) which may provide a longer duration than phenylephrine. Such actives include, but are not limited to, acetaminophen, ibuprofen and naproxen and salts and derivatives thereof.

Example 1: Preparation of Formulation Containing Coated Phenylephrine Extended Release Particles

[0075] A formulation that contains phenylephrine particles coated with a polymer coating was prepared. The formulation, which provides release of phenylephrine over an extended period of time, has proven to be stable at 25° C./60% RH for 24 months and at 40° C./75% RH for 3 months. Many granulated formulations of phenylephrine are not stable over time and undergo significant degradation.

[0076] A batch of 3.203 kg of coated phenylephrine particles was prepared according to the formula in Table 1. The quantitative and batch formulas, respectively, are represented in Table 1.

TABLE-US-00001 TABLE 1 Coated Extended Release Phenylephrine Particles.sup.1 Weight/Unit Weight Weight/Batch Component Dose (mg) % (w/w) (kg) Phenylephrine HCl USP  20.00  5.30 0.1699 Pregelatinized Modified  91.22  24.17 0.7739 Starch NF Ethyl Acrylate and Methyl 134.66  35.68.sup.2 1.1427 Methacrylate Copolymer Dispersion (Eudragit ® NE 30D) NF Ethylcellulose (Ethocel ®  45.33  12.01 0.3846 Standard Premium 10) NF Acetyltributyl Citrate NF  9.06  2.40 0.0769 Magnesium Stearate NF  9.06  2.40 0.0769 Ethylcellulose Aqueous  66.27  17.56.sup.2 0.5625 Dispersion (Aquacoat ECD ® ).sup.3 NF Colloidal Silicon Dioxide  1.77  0.47 0.0150 NF Purified Water.sup.4 USP — — — Acetone.sup.4 NF — — — Isopropyl Alcohol.sup.4 NF — — — TOTAL 100.00 3.203 .sup.1A unit dose of the particles containing 20 mg phenylephrine HCl is approximately 377.4 mg. Actual weight is dependent on the assayed amount of phenylephrine HCl in the particles. .sup.2Solids weight. .sup.3Contains ethylcellulose, cetyl alcohol and sodium lauryl sulfate. .sup.4Purified water, acetone and isopropyl alcohol are removed during processing.

Layering of Particles:

[0077] 1. Purified water USP was added to a suitably sized stainless steel container.

[0078] 2. Ethyl acrylate NF and methyl methacrylate copolymer dispersion NF (Eudragit® NE 30D) was added with gentle agitation.

[0079] 3. Phenylephrine HCl USP was added while mixing with agitation and mixed.

[0080] 4. Step 3 mixture was used to coat (layer) pregelatinized modified starch NF.

Drying and Screening:

[0081] 5. The layered phenylephrine HCl/pregelatinized modified starch from Step 4 was dried and screened through a #20 screen.

Coating of Layered Particles with Ethylcellulose Coating Solution:

[0082] 6. The following were added in the order as they appear to a suitably sized container with gentle agitation: isopropyl alcohol USP, followed by acetone NF, followed by acetyltributyl citrate NF.

[0083] 7. Ethylcellulose NF (Ethocel® Standard Premium 10) was added with agitation and mixed until a clear solution was formed.

[0084] 8. Magnesium stearate was added to the solution with agitation.

[0085] 9. The screened layered phenylephrine/pregelatinized modified starch particles from Step 5 were coated with the solution from Step 8 using a suitable fluid bed coating unit fitted with a Wurster insert.

Curing:

[0086] 10. The particles from Step 9 were cured in an oven.

Coating of Ethocel® Coated Particles with Eudragit® NE30D and Aquacoat ECD®:

[0087] 11. Eudragit® NE30D was added followed by purified water USP and ethylcellulose aqueous dispersion NF (Aquacoat ECD®) to a suitably sized container and mixed with gentle agitation.

[0088] 12. The Ethocel® coated layered particles from Step 10 were coated with the coating solution using a suitable fluid bed coating unit fitted with a Wurster insert.

[0089] 13. The coated particles from Step 12 were mixed with colloidal silicon dioxide NF.

Curing:

[0090] 14. The particles from Step 13 were cured in an oven.

Dissolution Analysis

[0091] The coated phenylephrine particles from Step 14 were analyzed for dissolution from 0 to 14 hours using the apparatus described in United States Pharmacopeia <General Chapter <711> Dissolution>, Apparatus II, rotating paddles, utilizing UV detection at 274 nm. The dissolution media was 750 mL of 0.1N HCl for the first hour and then was 1000 mL of a 0.05 M sodium phosphate buffer, pH 6.8, for the second to the fourteenth hour. The temperature was 37° C. and the rotation speed was 50 rpm. The dissolution showed that the percent of phenylephrine released versus a standard prepared at 100% of the amount of phenylephrine in the formulation was less than or equal to 50% in 1 hour, greater than or equal to 30% in 3 hours and greater than or equal to 50% in 8 hours. The method employed is below and the results are shown in Table 2 below.

Dissolution Method USP Apparatus (2 Paddles, 50 Rpm)

[0092] 1. Verify that the dissolution media temperature has reached the target value (37° C.).

[0093] 2. Weigh out samples equivalent to 45 mg of phenylephrine HCl. Add samples (onto the surface of the medium solution) to each vessel containing 750 mL of 0.1N hydrochloric acid and start the dissolution test with the paddle speed at 50 rpm. After 1 hour of operation in 0.1N hydrochloric acid, complete the 1 hour time point measurement. Proceed immediately to the buffer stage by adding 250 mL of 0.20 M tribasic sodium phosphate. The pH of the buffer medium is 6.8±0.05.

[0094] 3. Measure the UV absorbance of phenylephrine HCl released in the medium by using a LEAP fiber optic system with in line probes for UV measurement at 274 nm.

[0095] 4. The amount of phenylephrine HCl dissolved can be determined using the UV absorbance of the sample solution under test in comparison with that of a standard solution at the wavelength of 274 nm. The amount of phenylephrine HCl dissolved can also be determined using the assay method below.

TABLE-US-00002 TABLE 2 Time (hours) % Dissolution  1 10%-30%  2 30%-50%  3 50%-70%  4 60%-80%  6 75%-95%  8 85%-100% 10 90%-100% 12 90%-100% 14 90%-100%

Assay Method

Sample Preparation

[0096] 1. Accurately weigh approximately 1600 mg of phenylephrine HCl particles and transfer into a 200-mL volumetric flask. (It is recommended to add 1 mL of 1% acetic acid/water solution to wet the particles to avoid the formation of solid clumps).

[0097] 2. Add 70 mL of 1% acetic acid/acetonitrile solution; shake the flask on a platform shaker at low speed for 1 hour. Note: swirl the flask periodically to remove the particles collected above the solvent level.

[0098] 3. Add about 50 mL of 1% acetic acid/water solution to the flask and continuously shake the flask at low speed for 1 hour.

[0099] 4. Dilute to volume with 1% acetic acid/water solution and mix well.

[0100] 5. Filter an aliquot using a 0.45 μm Millipore Millex PVDF filter. Discard the first 1-2 mL of filtrate before collection the filtrate for the further dilution.

[0101] 6. Pipet 6 mL of the filtrate into a 50-mL volumetric flask, dilute to volume with 1% acetic acid/water and mix well.

Analysis of Phenylephrine

[0102] Inject standards (0.05 mg/mL of phenylephrine HCl in 1% acetic acid/water) and samples onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography. Determine the assay of phenylephrine HCl using the peak areas of the sample solutions under test in comparison with the peak areas of the standard solution.

TABLE-US-00003 HPLC Chromatographic Conditions Column Phenomenex Luna SCX, 100 mm length × 4.6 mm ID, 5 μm particle size, 100 Angstrom pore size Mobile Phase 25 mM Sodium Acetate Trihydrate Buffer (pH 4.6):Acetonitrile (65:35, v/v) Mobile Phase Program Isocratic Detector UV, 214 nm Flow Rate 2.0 mL/min Injection Volume 100 μL Column Temperature Ambient Suggested Run Time 7 minutes Approx. Retention PHE 5 min Time

Degradation Products Method

Sample Preparation

[0103] 2. Accurately weigh approximately 1600 mg of phenylephrine HCl particles and transfer into a 200-mL volumetric flask. (It is recommended to add 1 mL of 1% Acetic Acid/water Solution to wet the particles to avoid the formation of solid clumps).

[0104] 2. Add 70 mL of 1% acetic acid/acetonitrile solution; shake the flask on a platform shaker at low speed for 1 hour. Note: swirl the flask periodically to remove the particles collected above the solvent level.

[0105] 3. Add about 50 mL of 1% acetic acid/water solution to the flask and continuously shake the flask at low speed for 1 hour.

[0106] 4. Dilute to volume with 1% acetic acid/water solution and mix well.

[0107] 5. Filter an aliquot using a 0.45 μm Millipore Millex PVDF filter. Discard the first 1-2 mL of filtrate before collection the filtrate for the further dilution.

[0108] 6. Pipet 6 mL of the filtrate into a 50-mL volumetric flask, dilute to volume with 1% acetic acid/water and mix well.

Analysis of Phenylephrine

[0109] Inject standards (0.00025 mg/mL of phenylephrine HCl in 1% acetic acid/water) and samples onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography Determine the amount of the degradation products of phenylephrine HCl using the peak areas of the sample solutions under test in comparison with the peak areas of the standard solution.

TABLE-US-00004 HPLC Chromatographic Conditions Column Supclco Ascentis RP-Amide, 250 mm length × 4.6 mm ID, 5 μm particle size, 100 Angstrom pore size Mobile Phase A: [100 mM Ammonium Formate Buffer pH 2.9:Acetonitrile (99:1)] B: [100 mM Ammonium Formate Buffer pH 2.9:Acetonitrile (50:50)] Mobile Phase Linear Gradient Program Program Time A (% B (% Flow (minutes) Volume) Volume) 1.0  0 100  0 1.0 10 100  0 1.0 13  91  9 1.0 21  45  55 1.0 38  25  75 1.0 43  0 100 1.0 44 100  0 1.0 50 100  0 Detector UV, 270 nm Injection 100 μL Volume Column Ambient Temperature Suggested 50 minutes Run Time Approx. 4,6-ISOQUIN  5.4 min Retention 4,8-ISOQUIN  6.7 min Time PHE-ONE  9.4 min 3HOBA 25.7 min

Example 2: Preparation of Coated Phenylephrine Resinate Extended Release Particles

[0110] Particles that contain phenylephrine and a cationic exchange resin were prepared and further coated with a semipermeable membrane. The ratio of the amounts of the coating ingredients, which can be varied to some extent, can be, e.g., cellulose acetate:hydroxypropylcellulose 2:1, 3:1, 4:1 or 5:1. The coating level, which can be varied to some extent, can be, e.g., 50%, 45%, 40%, 35%, 30%, 25% or 20% by weight of the coated particle. Most of the particles in the starting cation exchange resin had particle sizes between about 74 μm and about 177 μm (microns).

[0111] The phenylephrine resinate particles, which provide release of phenylephrine over an extended period of time, have proven to be stable at 25° C./60% RH for 24 months and at 40° C./75% RH for 3 months. Many granulated formulations of phenylephrine are not stable over time and undergo significant degradation.

[0112] A batch of 3.846 kg of coated phenylephrine resinate particles was prepared according to the formula in Table 3. The quantitative formula and batch formula are represented in Table 3 and Table 4, respectively.

TABLE-US-00005 TABLE 3 Coated Phenylephrine Resinate Quantitative Formula Formula A.sup.1 Formula B.sup.1 Weight Component mg/Unit mg/Unit % (w/w) Phenylephrine HCL USP 20.00 15.00 19.50.sup.2 Sodium Polystyrene Sulfonate 38.32 28.76 45.50 USP (most of the particles have a particle size of about 74 μm to about 177 μm) Cellulose Acetate NF 22.10 16.59 26.25 Hydroxypropyl Cellulose NF  7.37  5.53  8.75 Acetone NF3 — — — Purified Water USP.sup.3 — — —

[0113] 1: Unit doses of particles containing 20 mg (A) and 15 mg (B) phenylephrine HCl are approximately 84.2 mg and 63.2 mg respectively. Actual weight is dependent on the assayed amount of phenylephrine HCl in the particles.

[0114] 2: Quantity represents the free base (1 mg of phenylephrine HCl is equivalent to 0.821 mg of phenylephrine free base).

[0115] 3: Acetone and purified water are removed during processing.

TABLE-US-00006 TABLE 4 Coated Phenylephrine Resinate Batch Formula Weight Weight Component (kg)/Batch % (w/w) Phenylephrine free base.sup.1 0.750  19.5 Sodium Polystyrene Sulfonate USP (particle 1.750  45.5 size of about 74 μm to about 177 μm) Cellulose Acetate NF 1.0095  26.25 Hydroxypropyl Cellulose NF 0.3365  8.75 Acetone NF.sup.3 — — Purified Water USP.sup.3 — — Total 3.846 100.0

[0116] 1: One gram of phenylephrine hydrochloride is equivalent to 0.821 grams of phenylephrine free base.

[0117] 2: Acetone and purified water are removed during processing.

[0118] The coated phenylephrine resinate particles were produced using the following processing steps:

Screening:

[0119] 1. Sodium polystyrene sulfonate USP having desired particle size was passed through a 170 mesh screen and the fraction remaining on the screen was collected.

Washing:

[0120] 2. Sodium polystyrene sulfonate USP from Step 1 was dispersed in purified water and mixed.

[0121] 3. While mixing, a portion of the slurry from Step 2 was filtered and washed with purified water USP. Filtration was continued until most of the water was removed.

[0122] 4. The resin was transferred into a container.

[0123] 5. Steps 3 and 4 were repeated until all of the slurry was removed.

Drug Loading:

[0124] 6. Purified water USP was added into a suitably sized stainless steel container.

[0125] 7. While mixing, phenylephrine HCL was added to the container and mixed until dissolved.

[0126] 8. The washed resin from Step 5 was added with continuous mixing and mixed into the slurry.

[0127] 9. While mixing, a portion of the slurry from Step 8 was withdrawn and washed with purified water USP. Filtration was continued until most of the water was removed.

[0128] 10. The washed filtered phenylephrine resinate from Step 9 was transferred into a container.

[0129] 11. Steps 9 and 10 were repeated until all of the slurry was filtered.

Drying:

[0130] 12. The phenylephrine resinate was dried.

Preparation of the Coating Solution:

[0131] 13. Purified water USP and acetone NF were added to an appropriately sized stainless steel container.

[0132] 14. Hydroxypropylcellulose NF was slowly added to the container and mixed until dissolved. Cellulose acetate NF was slowly added and mixed until dissolved.

[0133] 15. Acetone NF was added until the solution was at the desired weight.

Coating:

[0134] 16. The phenylephrine resinate from Step 12 was coated with coating solution from Step 15 in appropriate fluid bed coating equipment fitted with a Wurster column.

[0135] 17. The coated phenylephrine resinate was discharged into a container.

Drying:

[0136] 18. The coated phenylephrine resinate was dried.

Screening:

[0137] 19. The dried coated phenylephrine resinate was screened through a U.S. standard #40 mesh screen and the fraction passing through the screen was collected.

Dissolution Analysis

[0138] The coated phenylephrine resinate particles from Step 19 were analyzed for dissolution from 0 to 14 hours using the apparatus described in United States Pharmacopeia <General Chapter <711> Dissolution>, Apparatus II, rotating paddles, utilizing UV detection at 274 nm. The dissolution media was 750 mL of 0.1N HCl for the first hour and was 1000 mL of a 0.05 M sodium phosphate buffer, pH 6.8, the second to the fourteenth hour. The temperature was 37° C. and the rotation speed was 50 rpm. The dissolution showed that the percent of phenylephrine released versus a standard prepared at 100% of the amount of phenylephrine in the formulation was less than or equal to 50% in 1 hour, greater than or equal to 30% in 3 hours and greater than or equal to 50% in 8 hours. The method employed is below and the results are shown in Table 5 below.

Dissolution Method USP Apparatus 2 (Paddles), 50 Rpm

[0139] 1. Verify that the dissolution media temperature has reached the target value.

[0140] 2. Add sample (onto the surface of the medium solution) to each vessel containing 750 mL of 0.1 N hydrochloric acid and start the dissolution test with the paddle speed at 50 rpm. After 1 hour of operation in 0.1 N hydrochloric acid, pull the 1 hour sample, and proceed immediately to the buffer stage by adding 250 mL of 0.20 M tribasic sodium phosphate. The pH of the media should be 6.8±0.05.

[0141] 3. Pull 10 mL of dissolution sample solutions from each vessel after 1 hour, 3 hours, 6 hours (optional), and 8 hours. Filter the sample solutions through Varian Full Flow Filters (10 μm).

[0142] 4. The amount of phenylephrine dissolved can be determined from UV absorbance in comparison with that of the standard solution at the wavelength of 274 nm. The amount of phenylephrine dissolved can also be determined using the phenylephrine assay method.

[0143] 5. Correct the amount dissolved at 3, 6, and 8 hours by adding the amount pulled at the earlier time points. Use DISSL Program (or equivalent) or manually correct for intermediate sampling.

TABLE-US-00007 TABLE 5 Time (hours) % Dissolution  1 20%-40%  2 40%-60%  3 50%-70%  4 60%-80%  6 75%-95%  8 80%-100% 10 90%-100% 12 90%-100% 14 90%-100%

Example 3: Particle Size Distribution Analysis

[0144] Several lots of resin and resin based particles were analyzed for particle size distribution. The samples included (1) Amberlite™ IRP69 resin, commercially available from The DOW Chemical Company, (2) unloaded resin having selected particle sizes (as prepared by Process A or Process B, respectively), and (3) loaded resinate particles (i.e., containing phenylephrine). The particle size distribution was analyzed using approximately 75 grams per sample in an FMC Syntron Sieve analyzer (FMC Technologies, Houston, Tex.), with settings at 90 volts for 11 minutes. The sieves were treated with a light dusting of magnesium stearate to prevent sticking during operation. The results are shown in Tables 6 and 7.

[0145] Particle size distribution can be analyzed on a smaller scale, using, e.g., an ATM L3P Sonic Sifter (Advantech Manufacturing, New Berlin, Wis.), which operates by using sonic pulses combined with mechanical agitation, to provide effective separation of particles.

TABLE-US-00008 TABLE 6 Particle Size Analysis of Unloaded Resin with “As is” and Selection Process A & B AL AL Lot 1 Lot 2 Lot 3 Lot 4 IRP69 IRP69 Process Process Process Process Mesh Size Lot 1.sup.1 Lot 2.sup.1 A.sup.2 A.sup.2 B.sup.3 B.sup.3 80 177 μm  0.1%  0.2%  0.1%  0.1%  0.2%  0.0% 100 149 μm  0.2%  0.3%  0.4%  0.4%  2.0%  0.2% 120 125 μm  0.8%  0.9%  3.4%  3.4%  19.8%  14.5% 140 105 μm  1.8%  1.7% 13.3%  15.1%  35.0%  34.1% 200 74 μm 23.2% 18.2% 80.9%  79.4%  41.7%  50.4% 325 44 μm 38.1% 37.4%  1.7%  1.5%  1.3%  0.8% PAN 0 μm 35.8% 41.4%  0.1%  0.0%  0.0%  0.0% >149 μm  0.4%  0.5%  0.6%  0.5%  2.2%  0.2% <74 μm 73.9% 78.7%  1.8%  1.5%  1.3%  0.8% >44 μm 64.2% 58.6% 99.9% 100.0% 100.0% 100.0% 74-177 μm 26.0% 21.1% 98.1%  98.4%  98.6%  99.1% 74-125 μm 24.9% 19.9% 94.2%  94.6%  76.8%  84.5% D.sub.10(μm).sup.4 7.7 7.0 76.7 76.8 79.6 78.9 D.sub.50(μm).sup.4 53.4 49.6 91.1 91.6 108.7 104.1 D.sub.90(μm).sup.4 94.4 91.9 115.5 116.6 139.0 132.4 Mean (μm) 54.8 51.5 94.4 94.6 108.8 105.0 .sup.1Amberlite ™ IRP69 “As is” commercially available .sup.2Amberlite ™ IRP69 after selecting particle size “Process A” .sup.3Amberlite ™ IRP69 after selecting particle size “Process B” .sup.4D.sub.10, D.sub.50 and D.sub.90 determined using GRADISTAT, Blott, S.J. and Pye, K. (2001) GRADISTAT: a grain size distribution and statistics package for the analysis of unconsolidated sediments. Earth Surface Processes and Landforms 26, 1237-1248.

TABLE-US-00009 TABLE 7 Particle Size Analysis of Loaded Resin with Selection Process A & B Lot 1 Lot 2 Lot 3 Lot 4.1 Lot 4.2 Lot 4.3 Lot 4.4 Process Process Process Process Process Process Process Mesh Size A.sup.1 A.sup.1 B.sup.2 B.sup.2 B.sup.2 B.sup.2 B.sup.2 80 177 μm  0.2%  0.2%  0.7%  0.1%  0.0%  0.1%  0.1% 100 149 μm  1.1%  1.2%  6.0%  1.0%  1.0%  1.1%  1.5% 120 125 μm  7.5%  8.1% 34.4% 33.8% 33.1% 34.9% 36.6% 140 105 μm 24.5% 32.3% 36.5% 36.7% 38.1% 36.1% 33.2% 200 74 μm 65.8% 53.1% 22.1% 27.7% 27.2% 26.8% 25.4% 325 44 μm  0.9%  4.2%  0.2%  0.8%  0.6%  1.0%  2.6% PAN 0 μm  0.0%  1.0%  0.0%  0.0%  0.0%  0.1%  0.7% >149 μm  1.3%  1.4%  6.7%  1.1%  1.0%  1.1%  1.5% <74 μm  0.9%  5.1%  0.2%  0.8%  0.7%  1.1%  3.3% >44 μm 100.0%  99.0% 100.0%  100.0%  100.0%  99.9% 99.3% 74-177 μm 98.9% 94.6% 99.1% 99.2% 99.3% 98.8% 96.7% 74-125 μm 90.3% 85.3% 58.6% 64.3% 65.3% 62.9% 58.6% D.sub.10(μm).sup.3 77.7 76.4 86.4 83.2 83.5 83.1 81.2 D.sub.50(μm).sup.3 96.1 99.5 119.8 116.3 116.2 116.8 117.4 D.sub.90(μm).sup.3 123.9 124.7 146.5 142.3 142.1 142.5 143.1 Mean (μm) 99.8 99.9 120.2 115.3 115.3 115.5 114.7 .sup.1Amberlite ™ IRP69 after selecting particle size “Process A” .sup.2Amberlite ™ IRP69 after selecting particle size “Process B” .sup.3D.sub.10, D.sub.50 and D.sub.90 determined using GRADISTAT, Blott, S.J. and Pye, K. (2001) GRADISTAT: a grain size distribution and statistics package for the analysis of unconsolidated sediments. Earth Surface Processes and Landforms 26, 1237-1248.

[0146] The impact of the drug-resin ratio on the efficiency of drug loading was observed. The results are shown in Tables 8 and 9 below.

TABLE-US-00010 TABLE 8 Impact of drug-resin ratio on drug loading process for representative drug loading batches Drug- Phenylephrine Loading Drug- Size Mixing resin free base Efficiency resin Range Resin Time Ratio (% w/w) in (%) of Ratio Lot (μm) (kg) (hr) (Slurry) Resinate Resinate (Resinate) Lot 4  75-150 10.000 4.5 0.90:1 33.46 67.8% 0.50:1 Process B (Table 6) Lot 3  75-150 8.798 3.0 0.75:1 31.19 73.8% 0.45:1 Process B (Table 6) Lot 4  75-150 10.000 3.0 0.55:1 27.39 83.8% 0.38:1 Process B (Table 6) Lot 4  75-150 10.000 3.0 0.55:1 26.99 82.1% 0.37:1 Process B (Table 6) Lot 4  75-150 10.000 3.0 0.55:1 28.03 86.5% 0.39:1 Process B (Table 6) Lot 4  75-150 9.000 3.0 0.55:1 27.62 84.8% 0.38:1 Process B (Table 6) Lot 4  75-150 9.000 3.0 0.55:1 27.74 85.3% 0.38:1 Process B (Table 6) Larger 212-420 0.500 3.0 0.69:1 30.36 76.7% 0.44:1 particle size Larger 212-420 4.551 3.0 0.55:1 27.80 85.5% 0.39:1 particle size Larger 212-420 4.750 3.0 0.55:1 27.97 86.2% 0.39:1 particle size

TABLE-US-00011 TABLE 9 Summary of drug-resin ratio impact on drug loading process Phenyl- ephrine Drug- free Loading Drug- Size Mixing resin base Efficiency resin Range Time Ratio (%) in (%) of Ratio (μm) (hr) (Slurry).sup.1 Resinate Resinate (Resinate) Comment(s)  75-150 3.0 0.55:1 27.55 84.5% 0.38:1 Average of 5 lots 3.0 0.75:1 31.19 73.8% 0.45:1 4.5 0.90:1 33.46 67.8% 0.50:1 212-420 3.0 0.55:1 27.89 85.8% 0.39:1 Average of 2 lots 3.0 0.69:1 30.36 76.7% 0.44:1 .sup.1Based on phenylephrine HCl in slurry. 2. Based on free base of phenylephrine.

Phenylephrine Assay Method—Measurements for Tables 8 and 9

Sample Preparation

[0147] 1. Accurately weigh suitable amount of coated phenylephrine resinate sample (containing equivalent of 25 mg of phenylephrine HCl) and transfer the weighed sample into a 500-mL volumetric flask. [0148] 2. Add 400 mL of diluent (1N HCl); shake the flask on a platform shaker at low speed for not less than 2 hours. [0149] 3. To ensure that particles do not collect above the solvent level, periodically rinse particulates into solution with diluent. [0150] 4. Dilute to volume with diluent and mix well. [0151] 5. Filter an aliquot using a 0.45 μm Millipore Millex PVDF syringe filter, or equivalent. Discard approximately the first 5 mL of filtrate before collection of the remainder in a HPLC vial for analysis.

Analysis of Phenylephrine

[0152] Inject standards (0.05 mg/mL of phenylephrine HCl in 1 N HCl) and samples onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography. Analytical results are valid if system suitability specifications are met.

TABLE-US-00012 HPLC Chromatographic Conditions Column Phenomenex Luna SCX, 100 mm length × 4.6 mm ID, 5 μm particle size, 100 Angstrom pore size Mobile Phase 25 mM Sodium Acetate Trihydrate Buffer (pH 4.6):Acetonitrile (65:35, v/v) Mobile Phase Program Isocratic Detector UV, 214 nm Flow Rate 2.0 mL/min Injection Volume 100 μL Column Temperature Ambient Suggested Run Time 7 minutes Approx. Retention PHE 5 min Time

Example 4—Dissolution Analysis of PK Study Material

[0153] The coated phenylephrine resinate particles employed in the first PK study, the second PK study and the PD study of Example 5 were analyzed for dissolution from zero to 8 hours using the method described in Example 2. The results are shown in Table 10A below.

TABLE-US-00013 TABLE 10A Dissolution Analysis (50 rpm) Coated Phenylephrine Coated Phenylephrine Resinate Sample from PK Resinate Sample from Study 1 and PK Study 2 PD Study 35% Coating Level 40% Coating Level 3:1 Cellulose Acetate NF 3:1 Cellulose Acetate NF Hydroxypropyl Hydroxypropyl Cellulose NF Cellulose NF Time (n = 6) (n = 6) point % Released % Released 1 Hour 20-40% 20-40% 3 Hours 50-70% 50-70% 6 Hours 75-95% 75-95% 8 Hours 80-100% 80-100%

[0154] The coated phenylephrine resinate particles employed in the first PK study, the second PK study and the PD study of Example 5 were also analyzed for dissolution from zero to 8 hours using the method described below. The results are shown in Table 10B below.

Dissolution Method USP Apparatus 2 (Paddles), 75 Rpm

[0155] 1. Verify that the dissolution media temperature has reached the target value.

[0156] 2. Add sample (directly into the medium solution using a suitable tube) to each vessel containing 750 mL of 0.1 N hydrochloric acid and start the dissolution test with the paddle speed at 75 rpm. After 1 hour of operation in 0.1 N hydrochloric acid, pull the 1 hour sample, and proceed immediately to the buffer stage by adding 250 mL of 0.20 M tribasic sodium phosphate. The pH of the media should be 6.8±0.05.

[0157] 3. Pull 10 mL of dissolution sample solutions from each vessel after 1 hour, 3 hours, 6 hours (optional), and 8 hours. Filter the sample solutions through Varian Full Flow Filters (10 μm).

[0158] 4. Determine the amount of phenylephrine dissolved from UV absorbance in comparison with that of the standard solution at the wavelength of 274 nm.

[0159] The amount of phenylephrine dissolved can also be determined using the phenylephrine assay method.

[0160] 5. Correct the amount dissolved at 3, 6, and 8 hours by adding the amount pulled at the earlier time points. Use DISSL Program (or equivalent) or manually correct for intermediate sampling.

TABLE-US-00014 TABLE 10B Dissolution Analysis (75 rpm) Coated Phenylephrine Coated Phenylephrine Resinate Sample from PK Resinate Sample from Study 1 and PK Study 2 PD Study 35% Coating Level 40% Coating Level 3:1 Cellulose Acetate NF 3:1 Cellulose Acetate NF Hydroxypropyl Hydroxypropyl Cellulose NF Cellulose NF Time (n = 6) (n = 6) point % Released % Released 1 Hour 20-40% 20-40% 3 Hours 70-90% 65-85% 6 Hours 80-100% 80-100% 8 Hours 90-100% 90-100%

Stability Analysis

[0161] The coated phenylephrine resinate particles employed in the first PK study and the second PK study of Example 5 were analyzed for stability after storage at 1 month at 25° C. and 60% relative humidity and at 1 month at 40° C. and 75% relative humidity. For all samples, the levels of 3-hydroxybenzaldehyde were less than or equal to 0.5%; the levels of phenylephrine 4.6 isomer (N-Methyl-4, 6-Dihydroxy-1,2,3,4-tetrahydroxyisoquinolone HCL) and phenylephrine 4.8 isomer (N-Methyl-4, 8-Dihydroxy-1,2,3,4-tetrahydroxyisoquinolone HCL) were less than or equal to 2.0%. The total degradation product quantitated as related to phenylephrine was less than or equal to 2.0% at 1 month in each environment.

Degradation Products Method

Sample Preparation for Degradation Products Method

[0162] 1. Accurately weigh suitable amount of coated phenylephrine resinate sample (containing equivalent of 25 mg of phenylephrine HCl) and transfer the weighed sample into a 500-mL volumetric flask. [0163] 2. Add 400 mL of diluent (1N HCl); shake the flask on a platform shaker at low speed for not less than 2 hours. [0164] 3. To ensure that particles do not collect above the solvent level, periodically rinse particulates into solution with diluent. [0165] 4. Dilute to volume with diluent and mix well. [0166] 5. Filter an aliquot using a 0.45 μm Millipore Millex PVDF syringe filter, or equivalent. Discard approximately the first 5 mL of filtrate before collection of the remainder in a HPLC vial for analysis.

Analysis of Phenylephrine for Degradation Products Method

[0167] Inject standards (0.00025 mg/mL of phenylephrine HCl in 1 N HCl) and samples onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography. Analytical results are valid if system suitability specifications are met.

TABLE-US-00015 HPLC Chromatographic Conditions Column Supclco Ascentis RP-Amide, 250 mm length × 4.6 mm ID, 5 μm particle size, 100 Angstrom pore size Mobile Phase A: [100 mM Ammonium Formate Buffer pH 2.9:Acetonitrile (99:1)] B: [100 mM Ammonium Formate Buffer pH 2.9:Acetonitrile (50:50)] Mobile Phase Linear Gradient Program Program Time A (% B (% Flow (minutes) Volume) Volume) 1.0  0 100  0 1.0 10 100  0 1.0 13  91  9 1.0 21  45  55 1.0 38  25  75 1.0 43  0 100 1.0 44 100  0 1.0 50 100  0 Detector UV, 270 nm Injection 100 μL Volume Column Ambient Temperature Suggested 50 minutes Run Time Approx. 4,6-ISOQUIN  5.4 min Retention 4,8-ISOQUIN  6.7 min Time PHE-ONE  9.4 min 3HOBA 25.7 min

Example 5: Clinical Studies

[0168] Two pharmacokinetic (PK) studies and a pharmacodynamic (PD) study were conducted.

[0169] A. First PK Study

[0170] A pilot study was conducted on sixteen subjects to determine the pharmacokinetic profile, bioavailability and metabolism of the coated extended release phenylephrine particles from Example 1 and the coated extended release phenylephrine resinate particles from Example 2. The subjects were assigned to receive four treatments after an overnight fast. There was a seven day washout between the four periods. In both cases, coated particles equivalent to a 20 mg phenylephrine HCl dose were administered in applesauce to healthy subjects. In addition, a combination of the extended release phenylephrine resinate particles from Example 2 and a commercial immediate-release liquid was evaluated. In the combination treatment, coated phenylephrine resinate particles equal to 15 mg phenylephrine HCl were administered in applesauce, and 10 mL of liquid equal to 5 mg phenylephrine HCl was administered by oral syringe.

[0171] The coated extended release phenylephrine particles from Example 1 and the coated extended release phenylephrine resinate particles from Example 2 were compared to McNeil-PPC, Inc.'s Non-Drowsy Children's Sudafed PE® Nasal Decongestant liquid (phenylephrine HCl 2.5 mg/5 mL). Table 11 summarizes the treatments in the first PK study.

TABLE-US-00016 TABLE 11 Treatment Group Total Dose Over 8 Hours A (test) coated ER phenylephrine resinate particles containing 20 mg phenylephrine B (test) coated ER phenylephrine HCl particles containing 20 mg phenylephrine C (test) coated ER phenylephrine resinate particles containing 15 mg phenylephrine and liquid IR phenylephrine HCl.sup.1 containing 5 mg phenylephrine D (reference) liquid IR phenylephrine HCl containing 10 mg phenylephrine .sup.1The unit dose of approximately 84.2 mg coated ER phenylephrine resinate paricles is equivalent to a 20 mgphenylephrine HCl dose. the unit dose of approximately 63.2 mg coated ER phenylephrine resinate particles is equivalent to a 15 mg phenylephrine HCl dose, and this latter unit dose was administered with 10 mL phenylephrine liquid 2.5 mg/5 mL, for a total of dose equivalent to a 20 mg phenylephrine HCl.

[0172] The coated ER phenylephrine resinate particles and the ER phenylephrine HCl particles were administered orally after folding the measured amount into a 4 oz cup of applesauce just prior to dosing. These single doses were swallowed without chewing, and followed with 240 mL of water. The phenylephrine HCl liquid was administered orally using an oral syringe. To standardize the conditions for dosing the reference treatment, the first of two oral 10 mg doses of liquid were followed with a 4 oz cup of applesauce and 240 mL of water.

[0173] Serial blood samples were collected into K3-EDTA tubes at specific time points over 8 or 16 hours after dose.

[0174] B. Second PK Study

[0175] A second pilot study was conducted: (i) to determine if 30 mg phenylephrine can attain similar maximum drug concentrations relative to two 10 mg doses of immediate-release phenylephrine given 4 hours apart; and (ii) to evaluate the ER PK profile and bioavailability of 20 mg phenylephrine and 1300 mg acetaminophen.

[0176] The second pilot study was conducted on twenty subjects to determine the pharmacokinetic profiles, bioavailability and metabolism of (1) a combination of (a) the coated extended release phenylephrine resinate particles from Example 2 equal to 15 mg phenylephrine HCl, (b) 10 mL phenylephrine liquid equal to 5 mg phenylephrine HCl and (c) 1300 mg extended release acetaminophen; (2) a combination of (a) the coated extended release phenylephrine resinate particles from Example 2 equal to 22.55 mg phenylephrine HCl and (b) phenylephrine liquid equal to 7.5 mg phenylephrine HCl; (3) a combination of (a) phenylephrine liquid equal to 20 mg phenylephrine HCl and (b) 1300 mg extended release acetaminophen; and (4) phenylephrine liquid equal to 20 mg phenylephrine HCl. Table 12 summarizes the treatments in the second PK study

TABLE-US-00017 TABLE 12 Treatment Group Total Dose Over 8 Hours A (test) coated ER phenylephrine resinate containing 15 mg phenylephrine and liquid IR phenylephrine HCl containing 5 mg phenylephrine and 1300 mg ER acetaminophen.sup.2 B (test) coated ER phenylephrine resinate containing 22.5 mg phenylephrine and liquid IR phenylephrine HCl containing 7.5 mg phenylephrine C (reference) liquid IR phenylephrine HCl containing 20 mg phenylephrine and 1300 mg ER acetaminophen D (reference) liquid IR phenylephrine HCl containing 20 mg phenylephrine .sup.2The extended release acetaminophen tablet formulation was the same granulation formulation that is commercially available in Tylenol ® Arthritis.

[0177] Serial blood samples were collected into K3-EDTA tubes at specified time points over 12 or 20 hours.

Results

[0178] Results for the PK studies appear in FIGS. 1-11 and in Table 13 below.

TABLE-US-00018 TABLE 13 Comparison of Mean Parameters for First PK Study A B C D (20 mg (20 mg (5 IR + 15 mg (10 mg PE PE ER IR Q4H × Resinate) HCl) Resinate) 2 doses) AUC* 1241.7 1162.6 1237.8 1162.5 (pg-hr/mL) Cmax  208.4  219.4  230.8  458 (pg/mL) Tmax   2.5   2.8   1.97 Tmax 1 = 0.36 (hr) Tmax 2 = 4.54 Note: Treatments A, B and C = AUC over 16 hours. Treatment D = AUC over 8 hours [0179] Figures are rounded off

[0180] In sum, the results show that: [0181] The ER-IR blend containing 20 mg phenylephrine had a Cmax that was 50% of the 10 mg IR dose and an AUCinf that was 15% more than two 10 mg IR doses (20 mg). [0182] The ER-IR blend containing 30 mg phenylephrine had a Cmax that was 85% of the 10 mg IR dose and an AUCinf that was 61% more than two 10 mg IR doses (20 mg). [0183] The ER-IR Blend containing 20 mg phenylephrine and 1300 mg acetaminophen had a Cmax that was 80% of the 10 mg phenylephrine IR dose and an AUCinf that was 22% more than two 10 mg IR doses (20 mg).

[0184] The results demonstrate that the formulation of the present invention provides efficacy over an extended period of time.

[0185] These results also demonstrate that the formulation of the present invention is able to match the duration of extended release acetaminophen.

[0186] The results also demonstrate that phenylephrine exposure is increased and phenylephrine PK profile is improved relative to a 10 mg immediate release dose of phenylephrine when phenylephrine is combined with acetaminophen. This may be due to competition for gut wall metabolism leading to greater absorption of phenylephrine and no effect on acetaminophen; and extended release formulation providing greater absorption of phenylephrine due to avoidance of gut wall metabolism in lower GI tract.

[0187] C. Pharmacodynamic Study

[0188] A randomized, double-blind, placebo-controlled study was conducted to determine the efficacy of phenylephrine and phenylephrine-acetaminophen extended release formulations in subjects with congestion and pain symptoms due to upper respiratory tract infections. A 30 mg ER dose, a 45 mg ER dose and a 30 mg ER dose co-administered with 1300 mg acetaminophen were assessed and compared to placebo. In each example, the coated ER phenylephrine resinate particles of the invention were employed. The 30 mg ER dose, the 45 mg ER dose and the 30 mg ER dose co-administered with 1300 mg acetaminophen each performed well against placebo in severity score for (1) stuffy/congested nose; (2) sinus pressure/tenderness; and (3) head congestion from 0 to 12 hours on Day 1.

[0189] The foregoing examples are not intended to limit the scope of the present invention, which may be set out in the claims. In particular, various equivalents and substitutions will be recognized by those skilled in the art in view of the foregoing disclosure and these are contemplated to be within the scope of the invention.

REFERENCES

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