PROCESS FOR MANUFACTURING PHENYLEPHRINE RESINATE PARTICLES; PHENYLEPHRINE RESINATE PARTICLES; AND USE OF PHENYLEPHRINE RESINATE PARTICLES IN PHARMACEUTICAL FORMULATIONS
20210330614 · 2021-10-28
Inventors
- Vincent W. Chen (Upper Holland, PA, US)
- Shun-Por Li (Landsdale, PA, US)
- Edward A. Koch (Mohnton, PA, US)
- Der-Yang Lee (Flemington, NJ)
- Joel Waldman (Chalfont, PA, US)
Cpc classification
A61K9/2081
HUMAN NECESSITIES
A61K9/5042
HUMAN NECESSITIES
A61K9/5047
HUMAN NECESSITIES
International classification
A61K31/137
HUMAN NECESSITIES
A61K9/14
HUMAN NECESSITIES
Abstract
Phenylephrine particles suitable for solid, semi solid or liquid dosage forms are disclosed.
Claims
1.-18. (canceled)
19. A process for preparing a drug-resin complex, comprising: Step A: mixing purified water and resin in a container to form a first mixture; filtering the first mixture to form a wet cake containing resin; rinsing the wet cake containing resin with purified water; filtering the rinsed wet cake containing resin; Step B: mixing purified drug and water in a container to form a drug solution; Step C: mixing the filtered wet cake containing resin and a portion of the drug solution in a container to form a second mixture; filtering the second mixture to form a first loaded resinate; Step D: mixing the first loaded resinate and a portion of the drug solution in a container to form a third mixture; filtering the third mixture to form a second loaded resinate; Step E: optionally, repeating step D multiple times; and Step F: drying the loaded resinate to form the drug-resin complex.
20. The process of claim 19, wherein the drug is phenylephrine.
21. The process of claim 20, wherein the resin is a cation polystyrene sulfonate.
22. The process of claim 21, wherein the cation polystyrene sulfonate comprises particle sizes of about 74 μm to about 177 μm prior to being combined with the phenylephrine.
23. The process of claim 22, wherein the drug resin complex comprises phenylephrine:resin in a ratio of greater than about 1:1.
24. The process of claim 23, wherein the drug resin complex comprises phenylephrine:resin in a ratio of about 1.4:1.
Description
BRIEF DESCRIPTION OF THE FIGURES
[0039]
[0040]
[0041]
[0042]
[0043]
[0044]
[0045]
[0046]
DETAILED DESCRIPTION OF THE INVENTION
[0047] 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.
[0048] 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
[0049] 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.
[0050] “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.
[0051] “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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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. They can also be dried via methods such as centrifugation, filtration, pressurized filtration, oven drying and fluid bed drying. The drug/resin complex has a ratio of phenylephrine to resin of greater than about 1:1, more preferably about 1:1 to about 1.8:1, more preferably about 1.2:1 to about 1.6:1, more preferably about 1.4:1.
[0057] “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.
[0058] 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.
[0059] 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.
[0060] “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.
[0061] 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.
[0062] As used herein, “pharmacodynamics” or “PD” is the study of the relationship between drug concentration at the site of action and the resulting effect.
[0063] As used herein, “pharmacokinetics” or “PK” is the study of the time course of drug absorption, distribution, metabolism and excretion.
[0064] As used herein, the term “phenylephrine” means benzynemethanol, 3-hydroxy-α-[(methylamino)methyl], and includes, but is not limited to pharmaceutically acceptable salts, esters, isomers or derivatives thereof.
[0065] 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.).
[0066] “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.
[0067] “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.
[0068] “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.
[0069] 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.
[0070] “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.
[0071] Specific embodiments of the present invention are illustrated by way of the following examples.
[0072] This invention is not confined to the specific limitations set forth in these examples.
EXAMPLES
[0073] 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.
[0074] A multiple step loading process was developed in order to (1) increase the phenylephrine loading level; and (2) increase the phenylephrine loading efficiency. Preferably, the process results in a phenylephrine loading efficiency of greater than about 40%, e.g., about 43%.
[0075] Dow literature for Amberlite™ IRP69 discloses that use of two or more loading stages, separating the resin from the liquid phase between stages, is an effective means of achieving maximum loading of drug on the resin. See www.dow.com/assets/attachments/business/process_chemicals/amberlite_and_duolite_pharmaceutical_grade_resins/amberlite_irp69/tds/am berlite_irp69.pdf. (2006). The present inventors have determined that they can achieve similar drug loading efficiency when using the same amount of drug in multiple loading steps, e.g., when using 1.4 parts drug/1 part resin, and employing a three step loading process; the amount of drug in each step can vary (e.g., 50%, 25% and 25% of the total amount of drug used; or e.g., 33¼%, 33¼%, 33¼% of the total amount of drug used) without significantly impacting loading efficiency.
[0076] Materials:
[0077] (1) Amberlite™ Ion-exchange Resin having particle sizes as set forth in Table A below:
TABLE-US-00001 TABLE A Particle Size Analysis of Sodium Polystyrene Sulfonate USP Resin using Dry Sieving Method derived from United States Pharmacopeia <811> and <786> Particle Size Measurement Determination/Unit (%) Target Amount (%) Result (%) % > 0.150 mm ≤7 3 % > 0.125 mm None (report value) 24 % > 0.100 mm None (report value) 70 % < 0.075 mm ≤5 2
[0078] (2) Phenylephrine HCl USP
Example 1: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading at 40° C.
[0079] The drug loading steps follow the sequence outlined in Table 1.
[0080] Part A: Washing of Resinate [0081] 1. 200.0 g of purified water was weighed in a suitable sized container. [0082] 2. While mixing, 70.0 g of Amberlite™ Ion-exchange Resin was slowly added and mixed for 15 minutes. [0083] 3. The contents were transferred to a filtering funnel and filtered under vacuum to form a wet cake. [0084] 4. The wet cake was rinsed with 200.0 g of purified water (Wash 1). [0085] 5. The wet cake was again rinsed with 200.0 g of purified water (Wash 2).
[0086] Part B: Drug Loading on Resin
[0087] Step A [0088] 1. 200.0 g of purified water was added to a suitable sized container and heated to 40° C. [0089] 2. 45.5 g of phenylephrine HCl was added and dissolved while mixing at 40° C. for 10 minutes. [0090] 3. The Amberlite™ Ion-exchange Resin was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0091] 4. After 60 minutes of mixing, the contents were filtered under vacuum.
[0092] Step B [0093] 1. 200.0 g of purified water was added to a suitable sized container and heated to 40° C. [0094] 2. 31.5 g of phenylephrine HCl was added and dissolved while mixing at 40° C. for 10 minutes. [0095] 3. The wet loaded resinate from Step A was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0096] 4. After 60 minutes of mixing, the contents were filtered under vacuum.
[0097] Step C [0098] 1. 200.0 g of purified water was added to a suitable sized container and heated to 40° C. [0099] 2. 10.5 g of phenylephrine HCl was added and dissolved while mixing at 40° C. for 10 minutes. [0100] 3. The wet loaded resinate from Step B was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0101] 4. After 60 minutes of mixing, the contents were filtered under vacuum. [0102] 5. The filtered contents were washed 5 times with 200 mL portions of purified water. The washed drug loaded resin was collected and allowed to oven dry at 40° C. for 24 hours.
TABLE-US-00002 TABLE 1 Formula Loading Steps; 1.25:1 Drug:resin ratio (87.5 g phenylephrine and 70 g of raw resinate) % Phenyl- Water Phenyl- % (w/w) Phenyl- ephrine Amount ephrine + Drug Step ephrine Amount (g) (g) Water (g) Solution Part B: 52 45.5 200 245.5 18.5 Step A Part B: 36 31.5 200 231.5 13.6 Step B Part B: 12 10.5 200 210.5 50 Step C Total 100 87.5 Part B NA 12.25* 200 210.5 6.125 *A drug/resin ratio at 1.6/1 represents 112 g of drug and 70 g of raw resinate. An additional 24.5 g of drug is needed to achieve 1.6/1 loading for the Part A resinate since the half of the drug loaded resinate was removed for analytical test. Therefore, only half the amount of 24.5 g of drug (12.5 g) was needed to complete the drug loading process to achieve 1.6/1 loading.
Example 2: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading at Room Temperature (25° C.)
[0103] The drug loading steps follow sequence outlined in Table 1.
[0104] Part A: Washing of Resinate [0105] 1. 200.0 g of purified water was weighed in a suitable sized container. [0106] 2. While mixing, 70.0 g of Amberlite™ Ion-exchange Resin was slowly added and mixed for 15 minutes. [0107] 3. The contents were transferred to a filtering funnel and filtered under vacuum to form a wet cake. [0108] 4. The wet cake was rinsed with 200.0 g of purified water (Wash 1). [0109] 5. The wet cake was again rinsed with 200.0 g of purified water (Wash 2).
[0110] Part B: Drug Loading on Resin
[0111] Step A [0112] 1. 200.0 g of purified water was added to a suitable sized container at room temperature. [0113] 2. 45.5 g of Phenylephrine HCl was added and dissolved while mixing at room temperature for 10 minutes. [0114] 3. The Amberlite™ Ion-exchange Resin was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0115] 4. After 60 minutes of mixing, the contents were filtered under vacuum.
[0116] Step B [0117] 1. 200 g of purified water was added to a suitable sized container at room temperature. [0118] 2. 31.5 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0119] 3. The wet loaded resinate from Step A was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. 4. After 60 minutes of mixing, the contents were filtered under vacuum.
[0120] Step C [0121] 1. 200 g of purified water was added to a suitable sized container at room temperature. [0122] 2. 10.5 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0123] 3. The wet loaded resinate from Step B was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0124] 4. After 60 minutes of mixing, the contents were filtered under vacuum. [0125] 5. The filtered contents were washed 5 times with 200 mL portions of purified water. The washed drug loaded resin was collected and allowed to oven dry at 40° C. for 24 hours.
Example 3: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading at Room Temperature (25° C.) with Lower Mixing Times
[0126] The steps for Example 2 were followed for Example 3, and the 60 minute mixing time for each step was reduced from 60 minutes to 15 minutes.
Example 4: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading at Room Temperature (25° C.) with Reduction in Filtration Steps
[0127] The steps for Example 2 were followed for Example 4, and the filtration steps in Step A and Step B were eliminated.
Example 5: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading at Room Temperature (25° C.) with Equal Amounts of Phenylephrine in Each Loading Step
[0128] The drug loading steps follow the sequence outlined in Table 2.
[0129] Part A: Washing of Resinate [0130] 1. 200.0 g of purified water was weighed in a suitable sized container. [0131] 2. While mixing, 70.0 g of Amberlite™ Ion-exchange Resin was slowly added and mixed for 15 minutes. [0132] 3. The contents were transferred to a filtering funnel and filtered under vacuum to form a wet cake. [0133] 4. The wet cake was rinsed with 200.0 g of purified water (Wash 1). [0134] 5. The wet cake was again rinsed with 200.0 g of purified water (Wash 2).
[0135] Part B: Drug Loading on Resin
[0136] Step A [0137] 1. 200.0 g of purified water was added to a suitable sized container at room temperature. [0138] 2. 29.2 g of Phenylephrine HCl was added and dissolved while mixing at room temperature for 10 minutes. [0139] 3. The Amberlite™ Ion-exchange Resin was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0140] 4. After 60 minutes of mixing, the contents were collected.
[0141] Step B [0142] 1. 200 g of purified water was added to a suitable sized container at room temperature. [0143] 2. 29.2 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0144] 3. The wet loaded resinate from Step A was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0145] 4. After 60 minutes of mixing, the contents were collected.
[0146] Step C [0147] 1. 200 g of purified water was added to a suitable sized container at room temperature. [0148] 2. 29.1 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0149] 3. The wet loaded resinate from Step B was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0150] 4. After 60 minutes of mixing, the contents were filtered under vacuum. [0151] 5. The filtered contents were washed 5 times with 200 mL portions of purified water. The washed drug loaded resin was collected and allowed to oven dry at 40° C. for 24 hours.
TABLE-US-00003 TABLE 2 Formula Loading Steps; 1.25:1 Drug:resin ratio (87.5 g phenylephrine and 70 g of raw resinate) % Phenyl- Water Phenyl- % (w/w) Phenyl- ephrine Amount ephrine + Drug Step ephrine Amount (g) (g) Water (g) Solution Part B: Step A 33.37 29.2 200 229.2 12.7 Part B: Step B 33.37 29.1 200 229.2 12.7 Part B: Step C 33.26 29.2 200 229.1 12.7 Total 100 87.5 * Drug/resin ratio: Step A: 29.2/70 = 0.417/1; Step B: 58.4/70 = 0.834/1; Step C: 87.5/70 = 1.25/1.
Example 6: Lab Based Production of Loaded Phenylephrine Resinate: 2× Loading at Room Temperature (25° C.)
[0152] The drug loading steps follow sequence outlined in Table 3.
[0153] Part A: Washing of Resinate [0154] 1. 200.0 g of purified water was weighed in a suitable sized container. [0155] 2. While mixing, 70.0 g of Amberlite™ Ion-exchange Resin was slowly added and mixed for 15 minutes. [0156] 3. The contents were transferred to a filtering funnel and filtered under vacuum to form a wet cake. [0157] 4. The wet cake was rinsed with 200.0 g of purified water (Wash 1). [0158] 5. The wet cake was again rinsed with 200.0 g of purified water (Wash 2).
[0159] Part B: Drug Loading on Resin
[0160] Step A [0161] 1. 200.0 g of purified water was added to a suitable sized container and heated to 40° C. [0162] 2. 45.5 g of Phenylephrine HCl was added and dissolved while mixing at room temperature for 10 minutes. [0163] 3. The Amberlite™ Ion-exchange Resin was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0164] 4. After 60 minutes of mixing, the contents were collected.
[0165] Step B [0166] 1. 200 g of purified water was added to a suitable sized container at room temperature. [0167] 2. 42.0 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0168] 3. The wet loaded resinate from Step A was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0169] 4. After 60 minutes of mixing, the contents were filtered under vacuum. [0170] 5. The filtered contents were washed 5 times with 200 mL portions of purified water. The washed drug loaded resin was collected and allowed to oven dry at 40° C. for 24 hours.
TABLE-US-00004 TABLE 3 Formula Loading Steps; 1.25:1 Drug:Resin ratio (87.5 g phenylephrine and 70 g of raw resinate) % Phenyl- Water Phenyl- % (w/w) Phenyl- ephrine Amount ephrine + Drug Step ephrine Amount (g) (g) Water (g) Solution Part B: Step A 52 45.5 200 245.5 18.5 Part B: Step B 48 42.0 200 242 17.4 Total 100 87.5 *Drug resin ratio: 45.5/70 = 0.65; 42/70 = 0.6; 0.65 + 0.6 = 1.25
Example 7: Lab Based Production of Loaded Phenylephrine Resinate: 1× Loading at Room Temperature (25° C.)
[0171] The drug loading steps follow sequence outlined in Table 4.
[0172] Part A: Washing of Resinate [0173] 1. 200.0 g of purified water was weighed in a suitable sized container. [0174] 2. While mixing, 70.0 g of Amberlite™ Ion-exchange Resin was slowly added and mixed for 15 minutes. [0175] 3. The contents were transferred to a filtering funnel and filtered under vacuum to form a wet cake. [0176] 4. The wet cake was rinsed with 200.0 g of purified water (Wash 1). [0177] 5. The wet cake was again rinsed with 200.0 g of purified water (Wash 2).
[0178] Part B: Drug Loading on Resin
[0179] Step A [0180] 1. 200.0 g of purified water was added to a suitable sized container and heated to 40° C. [0181] 2. 87.5 g of Phenylephrine HCl was added and dissolved while mixing at Room temperature for 10 minutes. [0182] 3. The Amberlite™ Ion-exchange Resin was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0183] 4. After 60 minutes of mixing, the contents were filtered under vacuum. [0184] 5. The filtered contents were washed 5 times with 200 mL portions of purified water. The washed drug loaded resin was collected and allowed to oven dry at 40° C. for 24 hours.
TABLE-US-00005 TABLE 4 Formula Loading Steps; 1.25:1 Drug:Resin ratio (87.5 g phenylephrine and 70 g of raw resinate) % Phenyl- Water Phenyl- % (w/w) Phenyl- ephrine Amount ephrine + Drug Step ephrine Amount (g) (g) Water (g) Solution Part B: Step A 100 87.5 200 287.5 30.4 Total 100 87.5 *Drug resinate ratio: 45.5/70 = 0.65; 42/70 = 0.6; 0.65 + 0.6 = 1.25
Example 8: Lab Based Production of Loaded Phenylephrine Resinate: 4× Loading at Room Temperature (25° C.)
[0185] The drug loading steps follow sequence outlined in Table 5.
[0186] Part A: Washing of Resinate [0187] 1. 200.0 g of purified water was weighed in a suitable sized container. [0188] 2. While mixing, 70.0 g of Amberlite™ Ion-exchange Resin was slowly added and mixed for 15 minutes. [0189] 3. The contents were transferred to a filtering funnel and filtered under vacuum to form a wet cake. [0190] 4. The wet cake was rinsed with 200.0 g of purified water (Wash 1). [0191] 5. The wet cake was again rinsed with 200.0 g of purified water (Wash 2).
[0192] Part B: Drug Loading on Resin
[0193] Step A [0194] 1. 200.0 g of purified water was added to a suitable sized container and heated to 40° C. [0195] 2. 21.9 g of Phenylephrine HCl was added and dissolved while mixing at room temperature for 10 minutes. [0196] 3. The Amberlite™ Ion-exchange Resin was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0197] 4. After 60 minutes of mixing, the contents were collected.
[0198] Step B [0199] 1. 200 g of purified water was added to a suitable sized container at room temperature. [0200] 2. 21.9 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0201] 3. The wet loaded resinate from Step A was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0202] 4. After 60 minutes of mixing, the contents were collected.
[0203] Step C [0204] 1. 200 g of purified water was added to a suitable sized container at Room temperature. [0205] 2. 21.9 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0206] 3. The wet loaded resinate from Step B was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0207] 4. After 60 minutes of mixing, the contents were collected.
[0208] Step D [0209] 1. 200 g of purified water was added to a suitable sized container at Room temperature. [0210] 2. 21.8 g of Phenylephrine HCl was added and dissolved while mixing for 10 minutes. [0211] 3. The wet loaded resinate from Step C was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0212] 4. After 60 minutes of mixing, the contents were filtered under vacuum. [0213] 5. The filtered contents were washed 5 times with 200 mL portions of purified water. The washed drug loaded resin was collected and allowed to oven dry at 40° C. for 24 hours.
TABLE-US-00006 TABLE 5 Formula Loading Steps; 1.25:1 Drug:resin ratio (87.5 g phenylephrine and 70 g of raw resinate) % Phenyl- Water Phenyl- % (w/w) Phenyl- ephrine Amount ephrine + Drug Step ephrine Amount (g) (g) Water (g) Solution Part B: Step A 25 21.9 200 221.9 9.9 Part B: Step B 25 21.9 200 221.9 9.9 Part B: Step C 25 21.9 200 221.9 9.9 Part B: Step D 25 21.9 200 221.9 9.9 Total 100 87.5 *Drug/resin ratio: Step A: 21.9/70 = 0.312/1; Step B: 43.8/70 = 0.625/1; Step C: 65.7/70 = 0.938/1; Step D: 87.5/1
Example 9: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading in Equal Amounts of Phenylephrine, with Reduced Mixing Times
[0214] The drug loading steps follow sequence outlined in Table 6.
[0215] Part A: Washing of Resinate [0216] 1. 114.0 g of purified water was weighed in a suitable sized container. [0217] 2. While mixing, 40.0 g of Amberlite™ Ion-exchange Resin was slowly added and mixed for 15 minutes. [0218] 3. The contents were transferred to a filtering funnel and filtered under vacuum to form a wet cake. [0219] 4. The wet cake was rinsed with 200.0 g of purified water (Wash 1). [0220] 5. The wet cake was again rinsed with 200.0 g of purified water (Wash 2).
[0221] Part B: Drug Loading on Resin
[0222] Step A [0223] 1. 114.0 g of purified water was added to a suitable sized container at room temperature. [0224] 2. 16.67 g of Phenylephrine HCl was added and dissolved while mixing at room [0225] temperature for 10 minutes. [0226] 3. The Amberlite™ Ion-exchange Resin was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0227] 4. After 30 minutes of mixing, the contents were filtered under vacuum.
[0228] Step B [0229] 1. 114.0 g of purified water was added to a suitable sized container at room temperature. [0230] 2. 16.67 g of Phenylephrine HCl was added and dissolved while mixing at room temperature for 10 minutes. [0231] 3. The wet loaded resinate from Step A was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0232] 4. After 30 minutes of mixing, the contents were filtered under vacuum.
[0233] Step C [0234] 1. 114.0 g of purified water was added to a suitable sized container at room temperature. [0235] 2. 16.66 g of Phenylephrine HCl was added and dissolved while mixing at room temperature for 10 minutes. [0236] 3. The wet loaded resinate from Step B was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0237] 4. After 30 minutes of mixing, the contents were filtered under vacuum. [0238] 5. The filtered contents were washed 5 times with 200 mL portions of purified water. The washed drug loaded resin was collected and allowed to oven dry at 40° C. for 24 hours.
TABLE-US-00007 TABLE 6 Formula Loading Steps; 1.25:1 Drug:resin ratio (50.0 g phenylephrine and 40 g of raw resinate) % Phenyl- Water Phenyl- % (w/w) Phenyl- ephrine Amount ephrine + Drug Step ephrine Amount (g) (g) Water (g) Solution Part B: 33.37 16.67 114 130.27 12.7 Step A Part B: 33.37 16.67 114 130.27 12.7 Step B Part B: 33.26 16.66 114 130.26 12.7 Step C Total 100 50.0 *Drug/resinratio: Step A: 16.67/40 = 0.417/1; Step B: 33.34/40 = 0.834/1; Step C: 50/40 = 1.25/1
Example 10: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading in Equal Amounts of Phenylephrine, with Reduced Mixing Times
[0239] The drug loading steps follow sequence outlined in Table 6, with an additional lot of resin.
Example 11: Lab Based Production of Loaded Phenylephrine Resinate: 3× Loading in Equal Amounts of Phenylephrine, with Reduced Mixing Times
[0240] The drug loading steps follow sequence outlined in Table 6, with an additional lot of resin.
TABLE-US-00008 TABLE 7 Assay results for Phenylephrine: The examples above were tested for % phenylephrine to determine the amount loaded onto the resinate as a function of steps: % Phenylephrine Example Description Assay Example 1 3 Step Loading at 40° C. 42.70 Example 2 3 Step Loading at room temperature 42.96 Example 3 3 Step Loading at lower mixing times 42.28 Example 4 3 Step Loading with reduced filtration 39.99 steps Example 5 3 Step Loading with equal drug loading 43.01 amounts in each step Example 6 2 Step Loading at room temperature 41.76 Example 7 1 Step Loading at room temperature 37.42 Example 8 4 Step Loading at room temperature 43.87 Example 9 3 Step Loading with equal amounts and 43.2 reduced mixing times Example 9 (a) Example 9 after sieving above 100 mesh 43.18 Example 9 (b) Example 9 after sieving below 100 mesh 43.02 Example 10 3 Step Loading with equal drug loading 42.70 amounts in each step, new resin lot Example 11 3 Step Loading with equal drug loading 42.98 amounts in each step, new resin lot
Example 12 (A and B): Production Scale of Loaded Phenylephrine Resinate: 3× Loading in Equal Amounts of Phenylephrine, with Reduced Mixing Times
[0241] The drug loading steps follow sequence outlined in Table 8.
12A
[0242] Part A: Washing of Resinate [0243] 1. 36.0 kg of purified water was weighed in a 50 gallon kettle equipped with a pneumatic mixer. [0244] 2. While mixing, 18.0 kg of Amberlite™ Ion-exchange Resin (Anhydrous) resin was slowly added and mixed for 30 minutes. [0245] 3. The contents were transferred into a filtering chamber and filtered to form a wet cake. [0246] 4. The wet cake was rinsed with 4.0 kg of purified water (Wash 1), and filtered using compressed air. [0247] 5. The wet cake was again rinsed with 36.10 kg of purified water (Wash 2)
[0248] Part B: Drug Loading on Resin
[0249] Step A [0250] 1. 69.1 kg of purified water was added to a 55 gallon stainless steel tank equipped with a pneumatic mixer. [0251] 2. 123.94 kg of phenylephrine HCl was added and dissolved while mixing at room temperature for 10 minutes to form the phenylephrine solution. [0252] 3. 31.0 kg of Phenylephrine HCl solution from Step 2 was added to a 50 gallon kettle [0253] 4. The Amberlite™ Ion-exchange Resin was added while slowly mixing. [0254] 5. After 30 minutes of mixing, the contents were transferred to a filtration chamber and filtered using compressed air.
[0255] Step B [0256] 1. 31.0 kg of the phenylephrine solution from Step A (2) was added to a 50 gallon kettle at room temperature. [0257] 2. 35.45 kg of wet loaded resinate from Step A was added while slowly mixing. [0258] 3. After 30 minutes of mixing, the contents were transferred to a filtration chamber and filtered using compressed air.
[0259] Step C [0260] 1. 30.7 kg of the phenylephrine solution from Step A (2) was added to a 50 gallon kettle at room temperature. [0261] 2. 39.17 kg of wet loaded resinate from Step B was added while slowly mixing, and the mixer speed was adjusted to maintain a vigorous flow. [0262] 3. After 30 minutes of mixing, the contents were transferred to a filtration chamber and filtered using compressed air. [0263] 4. Washing #1: 22.0 kg of purified water was added to a filtration chamber containing the wet resinate from Step 3 and filtered using compressed air. [0264] 5. Washing #2: 22.0 kg of purified water was added to a filtration chamber containing the wet resinate from Step 4 and filtered using compressed air. [0265] 6. Washing #3: 22.0 kg of purified water was added to a filtration chamber containing the wet resinate from Step 5 and filtered using compressed air. [0266] 7. Washing #4: 22.0 kg of purified water was added to a filtration chamber containing the wet resinate from Step 6 and filtered using compressed air. [0267] 8. The wet resinate was transferred into a fluid bed dryer for drying at an inlet temperature of 140° F., a fluidizing air volume of 550 cfm and an end point of external air temperature of 110° F.
TABLE-US-00009 TABLE 8 Formula Loading Steps; 1.33:1 Drug:resin ratio (23.94 kg phenylephrine and 18 kg of raw resinate anhydrous) % Phenyl- Water Phenyl- % (w/w) Phenyl- ephrine Amount ephrine + Drug Step ephrine Amount (kg) (kg) Water (kg) Solution Part B: Step A 33.37 7.98 23.03 31.01 25.7 Part B: Step B 33.37 7.98 23.03 31.01 25.7 Part B: Step C 33.26 7.98 23.03 30.70 25.7 Total 100 23.94 *Drug/resin ratio: Step A: 7.98/18 = 0.443/1; Step B: 15.96/18 = 0.887/1; Step C: 23.94/18 = 1.33/1
TABLE-US-00010 TABLE 9 Assay results for Phenylephrine: Samples pulled and analyzed between each loading step % Sample for Phenylephrine Example analysis Assay Example 12: 3 Step Equal Drug Loading First Step 24.60 Example 12: 3 Step Equal Drug Loading Second Step 37.13 Example 12: 3 Step Equal Drug Loading Third Step 42.19
12B
[0268] Example 12A was repeated to obtain the data represented in
Discussion
[0269] The results above demonstrate that:
[0270] (1) a multiple step loading process increases the level of phenylephrine in the particles, i.e., 4-step>3-step>2-steps>single step when a fixed drug/resin ratio is applied;
[0271] (2) a rinse between the loading increases the level of phenylephrine in the particles due to the removal of counter ions;
[0272] (3) the drug/resin ratio is a factor determining the loading level while the temperature and mixing time have no significant impact;
[0273] (4) with 4 different lots of resin, no significant difference on the phenylephrine loading level was observed within the range of sodium content used in the study;
[0274] (5) similar results are achieved between lab-scale and pilot-scale, i.e., the process can be scaled up 450× with minimum modifications;
[0275] (6) resin particle size difference in this study does not affect the loading efficiency;
[0276] (7) the first step of loading has higher efficiency, with each additional step, the increase on the loading efficiency decreases. This may be contributed from the availability and accessibility of the binding sites in the resin;
[0277] (8) a single step loading process seems to have limitations on the phenylephrine loading level at higher drug/resin ratio, while a multiple step process achieves higher loading level with same drug/resin ratio.
Conclusion
[0278] With varied drug/resin ratios, targeted drug loading levels of phenylephrine HCl can be obtained with higher efficiency via a multiple-step loading process. Multiple-step loading can reduce the cost and usage of the ion-exchange resin in the formulation and achieve the loading level required to meet the published regulatory limit for polistirex resin in a dosage form.
Example 13: Coating of Phenylephrine Resinate Particles
[0279] The impact of higher loading of phenylephrine via the multiple step loading process on in-vitro drug release profiles using a cellulose acetate/hydroxypropyl cellulose co-polymeric system (CA/HPC) was observed.
[0280] Experiments were performed using the same coating formula (i.e., CA/HPC: 3/1 in a 90/10 acetone/water system) and similar process equipment and parameters on two single step loaded resinates (phenylephrine levels of 29% and 38% w/w, respectively) and one multiple-step loaded resinate (phenylephrine level of 43% w/w)
[0281] The formulation performance was evaluated by the in-vitro release profile of phenylephrine up to 24 hours.
[0282] Part A: Preparation of Coating Solution
[0283] A coating solution containing cellulose actetate and hydroxypropylcellulose in a ratio of 3:1 was prepared as follows. [0284] 1. Purified water and acetone were added to a stainless steel container. [0285] 2. Hydroxypropylcellulose NF was slowly added to the container and mixed until dissolved. [0286] 3. Cellulose Acetate NF was slowly added and mixed until dissolved. [0287] 4. Acetone was added until the solution was at the desired weight. [0288] 5. The final solution concentration was 6% solids in solution (4.5% cellulose acetate and 1.5% hydroxypropylcellulose).
[0289] Part B: Coating of Resinate Particles
[0290] Phenylephrine resinate particles prepared according to Tables 10 and 11 were coated using a fluid bed 18 inch Wurster coating unit. The following process parameters were followed during coating: [0291] Inlet Air temperature: 38° C. [0292] Spray rate of solution: 220 g/minute [0293] Outlet air temp: 28° C. [0294] Atomization air pressure: 80 psi [0295] Initial coating change weight: 19.0 kg [0296] Dewpoint: 32° C. (0° C.) is desired [0297] Drying conditions to less than 500 ppm acetone (e.g., 24-48 hours at 60° C. in an oven) [0298] Screening to remove agglomerations
TABLE-US-00011 TABLE 10 Formulation information for Pilot-Scale Coating Operations Utilizing Drug Loaded Resin from One-Step Loading Process Coated Drug Loaded Resinate Drug Loaded Resinate CA/HPC Drug Drug- Expt Coating Level Assay Loading Assay Resin # (%) (% w/w) Process (% w/w) Ratio 1 40 16.33 One-Step 29.22 0.59/1 2 40 16.93 One-Step 29.46 0.59/1 3 40 21.95 One-Step 38.19 1.60/1
TABLE-US-00012 TABLE 11 Formulation Information for Pilot-Scale Coating Operations Utilizing Drug Loaded Resin from Three-Step Loading Process Coated Drug Loaded Resinate Drug Loaded Resinate CA/HPC Drug Drug- Expt Coating Level Assay Loading Assay Resin # (%) (% w/w) Process (% w/w) Ratio 4* 35 27.7 Three-Step 42.49 1.33/1 5 40 24.7 Three-Step 42.43 1.33/1 6 45 22.1 Three-Step 42.19 1.33/1 7 50 19.9 Three-Step 42.49 1.33/1 *In-Process Sample
[0299] Tables 12 and 13 are set forth below.
[0300] The quantitative formula and batch formula are represented in Table 12 and Table 13, respectively.
TABLE-US-00013 TABLE 12 Coated Phenylephrine Resinate Quantitative Formula Formula.sup.1 Weight % Component Mg/Unit (w/w) Phenylephrine HCL USP 22.5 24.7 Sodium Polystyrene Sulfonate USP 26.40 35.3 (Amberlite ™ Ion-exchange Resin) Cellulose Acetate NF 22.43 30 Hydroxypropyl Cellulose NF 7.48 10 Acetone NF.sup.3 — — Purified Water USP.sup.3 — — .sup.1Unit doses of particles containing 22.5 mg phenylephrine HCL is approximately 74.48 mg. Actual weight is dependent on the assayed amount of phenylephrine HCL in the particles. .sup.2Quantity represents the free base (1 mg of phenylephrine HCL is equivalent to 0.821 mg of phenylephrine free base). .sup.3Acetone and purified water are removed during processing.
TABLE-US-00014 TABLE 13 Coated Phenylephrine Resinate Batch Formula Weight Weight % Component (kg/Batch) (w/w) Phenylephrine free base.sup.1 7.41 24.7 Sodium Polystyrene Sulfonate USP 10.59 35.3 (Amberlite ™ Ion-exchange Resin) Cellulose Acetate NF 9.00 30.0 Hydroxypropyl Cellulose NF 0.30 10.0 Acetone NF.sup.2 — — Purified Water USP.sup.2 — — Total 30.00 100 .sup.1One mg of phenylephrine HCL is equivalent to 0.821 mg of phenylephrine free base. .sup.2Acetone and purified water are removed during processing.
Example 14: Dissolution Analysis of Coated Phenylephrine Resin Particles
[0301] The coated phenylephrine resinate particles from Example 13 were tested for dissolution from 0 to 24 hours using the apparatus described in the 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 0.05M sodium phosphate buffer, pH 6.8, for the second to the 24.sup.th hour. The temperature was 37° C. and rotation speed was 75 rpm. The dissolution showed that the percent 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.
[0302] The following steps were followed for the Dissolution Method using USP Apparatus 2 (Paddles),
[0303] 75 rpm:
[0304] 1. Verify that the dissolution media temperature has reached the target value.
[0305] 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 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.
[0306] 3. Pull 10 mL of dissolution sample solutions from each vessel after 1 hour, 2 Hours, 3 hours, 6 hours (optional), 8 hours, 12 hours and 24 hours. Filter the sample solutions through Varian Full Flow Filters (10 μm).
[0307] 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.
[0308] 5. Correct the amount dissolved at 3, 6, and 8 hours by adding the amount pulled at the earlier time points. Use a dissolution program (or equivalent) or manually correct for intermediate sampling and removal of samples.
[0309] Table 14 is set forth below.
TABLE-US-00015 TABLE 14 Formulation Composition Loading Drug/ Resin Ratio 1.33/1 1.33/1 1.33/1 1.33/1 0.59/1 1.60/1 Coating Level 35.00% 40.00% 45.00% 50.00% 40.00% 40.00% Pheylephrine 27.70% 24.70% 22.10% 19.90% 16.93% 21.95% (Base) IRP-476 Resin 37.30% 35.30% 32.90% 30.10% 43.07% 38.05% Cellulose 26.25% 30.00% 33.75% 37.50% 30.00% 30.00% Acetate Hydrocypropyl 8.75% 10.00% 11.25% 12.50% 10.00% 10.00% Cellulose
TABLE-US-00016 TABLE 15 Coating Solution Composition Material % (w/w) Cellulose Acetate NF 4.50% Hydroxypropyl Cellulose EF 1.50% Acetone NF 84.60% Purified Water USP 9.40%
[0310] Results
TABLE-US-00017 TABLE 16 Formulation for Tablet Containing 22.5 mg of Drug from Coated Drug Resin (ER Portion) plus 7.5 mg of Phenylephrine HCL (IR Portion) 22.5 mg of Drug from ER 7.5 mg Coated Drug Loaded Resinate of Drug Amount from IR of Amount Phenylephrine CA/HPC coated of Drug HCL Coating Resinate Resinate Loaded Amount Tablet # Level (%) (mg) (mg) Resinate (mg) 1 40 74.8 26.4 3-Step 7.5 Loading Process Clinical* 40 106.9 45.7 1-Step 7.5 Loading Process
Discussion
[0311] After coating, the phenylephrine levels from the multiple-step loading remain higher than the single-step process at the same coating level (40%). [0312] At a certain coating level, e.g. 40%, the higher phenylephrine loading level has a slightly faster release rate than the lower loading level. [0313] Duplicated results were observed at the same phenylephrine loading and polymer coating level. [0314] For Multiple-Step loading: [0315] The release rate is inversely proportional to the phenylephrine loading level, i.e., the higher the coating level (from 35% to 50%), the slower the release rate (83% to 42% at 2 hour time point). [0316] Release profile from a given single step loaded resinate can be matched with a corresponding multiple-step loaded resinate via an adjusted coating level. [0317] The resin amount required in a single unit finished product can therefore be reduced from 45.7 to 26.4 mg and achieve the requirement to meet the published regulatory limit.
CONCLUSIONS
[0318] The results show that in the loading level ranges specified in the study, the phenylephrine HCl released from the coated polistirex particles was generally controlled by the coating level applied during the coating process while the loaded levels and numbers of steps applied in the drug loading process have no major impact. Minor adjustments of the coating levels and process parameters may be required, however, to achieve the same dissolution profile when switching from one loaded resinate to another.
[0319] With a similar release performance observed from this multiple-step, high loading phenylephrine coated resinate, a 12-hour sustained release of phenylephrine HCl formulation can therefore be achieved to comply with the excipient guideline on ion-exchange resin of 25 mg/day usage.
[0320] 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.
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