WO2003088952A1

WO2003088952A1 - Sustained release of guaifenesin combination drugs

Info

Publication number: WO2003088952A1
Application number: PCT/US2003/011500
Authority: WO
Inventors: Robert D. Davis; Ralph W. Blume; Donald Jeffrey Keyser
Original assignee: Adams Laboratories, Inc.
Priority date: 2002-04-15
Filing date: 2003-04-15
Publication date: 2003-10-30
Also published as: CA2481739A1; IL164438A0; EA007156B1; JP2005528402A; CN1655766A; ZA200409171B; AU2003237807A1; CN1655766B; EP1503739A4; CA2481739C; AU2003237807B2; JP5466346B2; EA200401369A1; MXPA04010225A; EP1503739A1

Abstract

The invention relates to a novel pharmaceutical modified release formulation of guaifenesin and optionally a second drug which is preferably selected from dextromethorphan and pseudoephedrine. The formulation may comprise a hydrophilic polymer, preferably a hydroxypropyl methylcellulose, and a waterinsoluble polymer, preferably an acrylic resin, in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1) by weight. This formulation capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject. The invention also relates to a modified release product which has two portions: a first portion having an immediate release formulation of guaifenesin and a second portion having a sustained release formulation of guaifenesin, wherein one or both portions further comprises dextromethorphan. The modified release product has a maximum guaifenesin serum concentration equivalent to that of an immediate release guaifenesin tablet, and is capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject.

Description

Agent's File Reference: 62808.000021

SUSTAINED RELEASE OF GUAIFENESIN COMBINATION DRUGS

Cross-Reference to Related Applications

[001] This application is a continuation-in-part of United States patent application number Not Yet Assigned which was filed on April 4, 2003 and United States patent application number Not Yet Assigned which was filed on April 4, 2003 both of which are a continuation-in-part of United States patent application number 10/121,706 which was filed on April 15, 2002 (pending) which is a continuation-in-part of United States patent no. 6,372,252 which was filed on April 28, 2000 as application no. 09/559,542 and issued on April 16, 2002 both of which are hereby incorporated in their entirety by reference.

BACKGROUND OF THE INVENTION

[002] The invention is directed to a modified release formulation for oral administration comprising combinations of guaifenesin and optionally at least one additional drug and methods of manufacture thereof. In particular, the invention is directed to a sustained release formulation which maintains a therapeutically effective blood concentration of guaifenesin and optionally the additional drug for a duration of about twelve hours. The invention further relates to combinations which demonstrate a maximum serum concentration equivalent to an immediate release tablet, while maintaining therapeutically effective blood concentration for about twelve hours.

[003] Sustained release pharmaceutical formulations provide a significant advantage over immediate release formulations to both clinicians and their patients. Sustained release dosage forms provide for fewer daily dose administrations than their immediate release counterparts. For example, a standard dosage regimen for a 400 mg immediate release drug with a short half- life, such as guaifenesin, requires administration three times within twelve hours to maintain adequate bioavailability to achieve the desired therapeutic effect. This results in a series of three serum concentration profiles in the patient showing a rapid increase of drug followed by a similar rapid decrease. As a result, patients are provided with only a short window of the appropriate blood Agent's File Reference: 62808.000021

concentration of the medicament for optimum therapy. A 1200 mg sustained release dosage form, on the other hand, may require administration once every twelve hours to achieve therapeutic effect. Sustained release dosage forms generally control the rate of drug absorption, to avoid excessive drug absorption while maintaining effective blood concentration of the drug to provide a patient with a consistent therapeutic effect over an extended duration of time.

[004] Besides reducing the frequency of dosing and providing a more consistent therapeutic effect, sustained release dosage forms generally help reduce side effects caused by a drug. Because sustained release dosage forms deliver the drug in slow, incremental amounts versus the cyclic high and low concentrations of immediate release formulations, it is easier for a patient's body to digest the drug, thereby avoiding undesirable side-effects. For patients who self-administer therapies, sustained release dosage forms generally result in greater compliance due to the lower frequency of dosing, lower quantity of dosage units to be consumed, and reduced undesired side-effects.

[005] Generally, sustained release formulations contain drug particles mixed with or covered by a polymer material, or blend of materials, which is resistant to degradation or disintegration in the stomach and/or in the intestine for a selected period of time. Release of the drug may occur by leeching, erosion, rupture, diffusion or similar actions depending upon the nature of the polymer material or polymer blend used.

[006] Conventionally, pharmaceutical manufacturers have used hydrophilic hydrocolloid gelling polymers such as hydroxypropyl methylcellulose (hydroxypropyl methylcellulose is also known as hypromellose and is used interchangeably throughout the application), hydroxypropyl cellulose, or Pullulan to formulate sustained release tablets or capsules. These polymers first form a gel when exposed to an aqueous environment of low pH thereby slowly diffusing the active medicament that is contained within the polymer matrix. When the gel enters a higher pH environment such as that found in the intestines, however, it dissolves resulting in a less controlled drag release. To provide better sustained release properties in higher pH environments, some Agent's File Reference: 62808.000021

pharmaceutical manufacturers use polymers which dissolve only at higher pHs, such as acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, and hydroxypropyl methylcellulose phthalate, either alone or in combination with hydrophilic polymers.

[007] Generally, these formulations are prepared by combining the medicament with a finely divided powder of the hydrophilic polymer, or the hydrophilic and water-insoluble polymers. These ingredients are mixed and granulated with water or an organic solvent and the granulation is dried. The dry granulation is then usually further blended with various pharmaceutical additives and compressed into tablets.

[008] Although these types of formulations have been successfully used to manufacture dosage forms that demonstrate sustained release properties, these formulations generally do not have the desired release profile or serum concentration of medicament over an extended period of time. These sustained release formulations generally result in a delay in the appearance of drug in the blood stream, thereby delaying therapeutic effect. Additionally, when the drug does appear, its maximum serum concentration (C_max) is lower than the maximum concentration required for the most effective therapeutic result. Furthermore, most formulations that claim twelve hour potency release almost all of their drug within six to eight hours, making the formulation less therapeutically effective towards the end of the twelve hour period. To prevent blood serum concentrations of drug from falling below a therapeutically effective level (C_m;_π) at extended time periods, many manufacturers increase the drug strength of the dosage form. The increase in drug strength, however, results in a concomitant increase in side-effects.

[009] Other pharmaceutical manufacturers have made tablets and capsules containing a combination of an immediate release formulation and a sustained release formulation to improve the release profile of certain sustained release dosage forms. Although this solution improves the C_max and length of time before the drug appears in the blood stream in some formulations, the extended therapeutic effect is not improved. Agent's File Reference: 62808.000021

[010] Furthermore, medicaments have different solubility properties and pH dependencies, which affect dissolution rate and bioavailability. Bioavailability can also be affected by a number of factors such as the amounts and types of adjuvants used, the granulation process, compression forces (in tablet manufacturing), surface area available for dissolution and environmental factors such as agitation in the stomach and the presence or absence of food. Due to these numerous factors, specific formulations play an important role in the preparation of prolonged action solid dosage forms, particularly in the preparation of solid dosage forms that achieve appropriate bioavailability for optimum therapeutic effect.

[011] Guaifenesin, 3-(2-methoxyphenoxy)-l,2-propanediol, is an expectorant that increases respiratory tract fluid secretions and helps to loosen phlegm. By reducing the viscosity of secretions, guaifenesin increases the efficiency of a cough reflex and of ciliary action in removing accumulated secretions from trachea and bronchi. Guaifenesin is readily absorbed from the intestinal tract and is rapidly metabolized and excreted in urine. Guaifenesin has a typical plasma half-life of approximately one hour. The rapid metabolism and excretion of guaifenesin provides only a short window of therapeutic effectiveness when immediate release dosage is used.

[012] Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory effects. At the recommended oral dose, it has little or no pressor effect in normotensive adults. Pseudoephedrine has been shown to have a mean elimination half-life of 4-6 hours.

[013] Dextromethorphan acts centrally to elevate the threshold for coughing. It has no analgesic or addictive properties. The major circulating metabolite is dextrorphan.

[014] The need exists for a sustained release dosage form of guaifenesin alone and in combinations, which are capable of sustaining therapeutic effective for Agent's File Reference: 62808.000021

extended periods of time. Further the need exists for sustained release dosage forms of guaifenesin alone and in combination which results in a C_max equivalent to that of an immediate release formulation, appears in the blood stream as quickly as an immediate release formulation, and sustains the therapeutic effect.

[015] SUMMARY OF THE INVENTION

The invention relates to strategies and designs in formulations of modified release guaifenesin and guaifenesin combination dosage forms. This invention provides sustained release pharmaceutical formulation comprising guaifenesin and at least one additional drug. The sustained release formulation (SR) may comprise a combination of at least one hydrophilic polymer and at least one water-insoluble polymer. The total weight ratio of hydrophilic polymer to water-insoluble polymer may be in a range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably in a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1). When a tablet comprising the sustained release formulation is exposed to an aqueous medium of low pH, such as that found in the stomach, the polymer combination gels causing guaifenesin and the drug(s) to diffuse from the gel. When the tablet passes to the intestines where an aqueous medium of higher pH is present, the gel begins to dissolve, thereby releasing guaifenesin and/or the drug(s) in controlled amounts. The tablet is capable of releasing therapeutically effective amounts of guaifenesin over an extended period, e.g. twelve or more hours and at least one additional drug immediately, over an extended period, or both.

[016] This invention also encompasses a modified release composition which comprises two portions (e.g. a bi-layer tablet, or capsule), an immediate release formulation (IR) and a sustained release formulation (SR). Each formulation comprises a specific quantity of guaifenesin and may optionally contain at least one additional drug. The immediate release formulation is formulated to dissolve in aqueous acidic medium, such as that found in the stomach, to quickly release guaifenesin contained within the portion, and optionally quickly release the at least one additional drug. The sustained release portion may comprise a Agent's File Reference: 62808.000021

combination of hydrophilic polymer and a water-insoluble polymer in a ratio range of about one-to-one (T.l) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably from about two-to-one (2:1) to about four-to-one (4:1). Likewise, the sustained release portion may also contain the additional drug(s).

[017] The invention also relates to sustained release preparations of the type described above in the form of capsules having beads or granules of both immediate release formulation and beads or granules of sustained release formulation. The beads may comprise a mixture of discrete beads each having only one of the SR or IR formulations or may comprise beads containing both SR and IR formulations associated in a single bead, or combinations of the foregoing. Alternatively, the sustained release formulation may comprise a core that is coated by a layer of the immediate release formulation to form a single tablet. For purpose of illustration only, the invention will be described in detail in the context of the bi-layered tablet embodiment. It should be understood that for either the immediate release and/or the sustained release portion the guaifenesin and optionally the additional drug may be mixed within the same matrix portion or comprise separate release portions which are then either compressed or mixed for capsules (e.g. comprise separate beads or granules) etc.

[018] A bi-layer tablet demonstrates a maximum serum concentration (C_maχ) and time of availability in the blood stream that are equivalent to an immediate release tablet. The bi-layer tablet also provides sustained release of guaifenesin over about a twelve hour period from one dose. The bi-layer tablet further maintains serum concentration levels of guaifenesin at a therapeutically effective level for about a twelve hour period without an increase in dosage strength. As the bi-layer tablet may also contain at least one additional drug, the additional drug can be formulated within the sustained release formulation, immediate release formulation, or both. In one embodiment, the bi-layer tablet maintains serum concentration levels of at least one additional drug at a therapeutically effective level for about a twelve hour period without an increase in dosage strength. Agent's File Reference: 62808.000021

[019] h another embodiment, the tablets and capsules of the invention provide a C_mi_n which is above the necessary therapeutically effective level for a period of 10 hours, more preferably 12 or more hours. In a more preferred embodiment, a tablet or capsule of the invention provides the above describe C_mi_n characteristics and provides the necessary C_max to mimic an immediate release product to obtain symptom relief. In a more preferred embodiment, the delivery system provides the above describe C_mj_n characteristics and provides the necessary C_max to mimic an immediate release product to obtain symptom relief within a substantially similar T_maχ period to an immediate release profile.

[020] In another embodiment of the invention, the delivery system provides a C_max which does not result in an equivalent C_max of an immediate release product but does provide a C_max which is therapeutically effect to relieve systems while reducing the likelihood of side effects due to an increased C_maχ-

[021] The invention also relates to methods of manufacturing sustained release formulations and bi-layer tablets. An example of a manufacturing method for a sustained release formulation comprises mixing a hydrophilic polymer and active ingredients in a mixer, adding water to the mixture and continuing to mix and chop, drying the mixture to obtain hydrophilic polymer encapsulated granules, milling and screening the resulting granulation, and blending it with various pharmaceutical additives, additional hydrophilic polymer, and water insoluble polymer. The formulation may then be tableted and may further be film coated with a protective coating which rapidly dissolves or disperses in gastric juices.

[022] An example of a bi-layer tablet manufacturing method comprises blending a quantity of guaifenesin and optionally, at least one drug with various excipients, colorants, and/or other pharmaceutical additives to form an immediate release formulation, separately blending another quantity of guaifenesin and optionally at least one drug with a hydrophilic polymer, a water-insoluble polymer, and various excipients, colorants, and/or other pharmaceutical additives to form a sustained release formulation, and compressing a quantity of the immediate release formulation with a quantity of the sustained release formulation to form a Agent's File Reference: 62808.000021

bi-layer tablet. The tablet may then optionally be coated with a protective coating which rapidly dissolves or disperses in gastric juices.

[023] Other objects, advantages and embodiments of the invention are described below and will be obvious from this description and practice of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[024] Figure 1 is a flow diagram depicting steps in a wet granulation method for manufacturing the sustained release formulation.

[025] Figure 2 is a flow diagram depicting steps in a dry granulation method for manufacturing the sustained release formulation.

[026] Figure 3 is a flow diagram depicting steps in a method for manufacturing the bi-layer tablet.

[027] Figure 4 is a graph demonstrating the dissolution profiles of tablets comprising two different sustained release formulations.

[028] Figure 5 is a graph demonstrating the dissolution profiles of a commercially available immediate release dosage form and two sustained release dosage forms of guaifenesin.

[029] Figure 6 is a graph demonstrating the plasma concentration of guaifenesin over time in healthy human volunteers who were dosed with three different guaifenesin formulations; a commercial immediate release formulation, and two different sustained release formulations (Lot 7B-32 and Lot 7B-31).

[030] Figure 7 is a graph demonstrating the plasma concentration of guaifenesin over time in healthy human volunteers from a commercially available immediate release tablet, a non-layered modified release tablet of the invention, and two bi- layered modified release tablets of the invention (one comprising 600 mg of immediate release formulation and 600 mg of sustained release formulation and the other one comprising 400 mg of immediate release formulation and 800 mg of sustained release formulation).

[031] Figure 8 is a graph demonstrating the dissolution profiles of four sustained release tablets: one tablet is non-layered, comprising 1200 mg of sustained release formulation; another tablet is bi-layered, comprising 600 mg of sustained release formulation and 600 mg of immediate release formulation; another tablet Agent's File Reference: 62808.000021

is bi-layered, comprising 800 mg of sustained release formulation and 400 mg of immediate release formulation; and yet another tablet is bi-layered comprising 1000 mg of sustained release formulation and 200 mg of immediate release formulation.

[032] Figure 9 is a graph demonstrating the plasma concentration of guaifenesin over an averaged 12 hour interval (taken from 11 twelve hour intervals over 5.5 days) in healthy human volunteers from an immediate release tablet and a bi- layered modified release tablet of the invention.

[033] Figure 10 is a graph demonstrating the plasma concentration of guaifenesin over time (the last twelve hour interval of the 11 twelve hour intervals described above) in healthy human volunteers from an immediate release tablet and a bi- layered modified release tablet of the invention.

[034] Figure 11 is a graph demonstrating the averaged plasma concentration of guaifenesin over a 16 hour period in 27 healthy human volunteers from 600 mg bi-layered modified release tablets of the invention administered to fasting volunteers, 1200 mg bi-layered modified release tablets of the invention administered to fasting volunteers, and 1200 mg bi-layered modified release tablets of the invention administered to volunteers who had been fed a high fat meal.

[035] Figure 12 is a graph demonstrating the dissolution profile of dextromethorphan HBr as measured by three different batches of a 1200 mg guaifenesin - 60 mg dextromethorphan tablet over a 12 hour period as measured by the weight percentage of dextromethorphan HBr dissolved over time.

[036] Figure 13 is a graph demonstrating the plasma concentration of guaifenesin following the administration of 1200 mg guaifenesin and 60 mg dextromethorphan HBr to volunteers separately and in formulations of the invention.

[037] Figure 14 is a graph demonstrating the plasma concentrations of dextromethorphan HBr following the administration of 1200 mg guaifenesin and 60 mg dextromethorphan HBr to volunteers in three different formulations. Agent's File Reference: 62808.000021

[038] Figure 15 is a graph demonstrating the plasma concentrations of the metabolite dextrorphan following the administration of 1200 mg guaifenesin and

60 mg dextromethorphan HBr to volunteers in three different formulations. [039] Figure 16 is a graph demonstrating the dissolution profile of pseudoephedrine HCl in three different batches of a 1200 mg guaifenesin - 120 mg pseudoephedrine HCl tablet formulation over a 12 hour period as measured by the percent pseudoephedrine HCl dissolved over time. [040] Figure 17 is a graph demonstrating the plasma concentration of guaifenesin following the administration of 1200 mg guaifenesin and 120 mg pseudoephedrine HCl to volunteers separately and in formulations of the invention. [041] Figure 18 is a graph demonstrating the plasma concentration of pseudoephedrine HCl following the administration of 1200 mg guaifenesin and

120 mg pseudoephedrine HCl to volunteers in three different formulations. [042] Figure 19 is a graph demonstrating the plasma concentration of three different 1200 mg guaifenesin dosages in groups A, B, and C of example 12. [043] Figure 20 is a graph demonstrating the plasma concentration of three different 120 mg pseudoephedrine dosages in groups A, B, and C of example 12. [044] Figure 21 is a graph demonstrating the plasma concentration of three different 1200 mg guaifenesin dosages for treatments A, B, and C of example

13. [045] Figure 20 is a graph demonstrating the plasma concentration of three different 120 mg pseudoephedrine dosages for treatments A, B, and C of example 13. [046] Figure 21 depicts guaifenesin concentrations of various formulations and dosage strength. [047] Figure 22 depicts pseudoephedrine plasma concentrations following administration of two different dose strengths of pseudoephedrine, as well as, different formulations. Agent's File Reference: 62808.000021

[048] Figure 23 depicts guaifenesin concentrations following administration of

1200 mg of guaifenesin with 120 mg pseudoephedrine hydrochloride in two different formulations following a high-fat meal. [049] Figure 24 depicts pseudoephedrine concentrations following administration of 1200 mg of guaifenesin with 120 mg pseudoephedrine hydrochloride in two different formulations following a high-fat meal. [050] Figure 25 depicts steady-state guaifenesin plasma concentrations following administration of 11 doses of 120 mg pseudoephedrine with 1200 mg of guaifenesin in two different formulations. [051] Figure 26 depicts steady-state pseudoephedrine plasma concentrations following administration of 11 doses of 120 mg pseudoephedrine with 1200 mg of guaifenesin in two different formulations. [052] Figure 27 depicts guaifenesin plasma concentrations following administration of 1200 mg of guaifenesin with and without the co-administration of 120 mg of pseudoephedrine. [053] Figure 28 depicts pseudoephedrine plasma concentrations following administration of 120 mg of pseudoephedrine with and without the co- administration of 1200 mg of guaifenesin. [054] Figure 29 depicts guaifenesin plasma concentrations following administration of an experimental 1200 mg guaifenesin- 120 mg pseudoephedrine formulation to volunteers under fed and fasted conditions. [055] Figure 30 depicts pseudoephedrine plasma concentrations following administration of an experimental 1200 mg guaifenesin-120 mg pseudoephedrine formulation to volunteers under fed and fasted conditions. [056] Figure 31 depicts guaifenesin dissolution profiles for various batches associated with the studies. [057] Figure 32 depicts pseudoephedrine dissolution profiles for various batches associated with the studies. [058] Figure 33 depicts guaifenesin plasma concentrations following the administration of 1200 mg guaifenesin with or without the co-administration of

60 mg dextromethorphan hydrobromide. Agent's File Reference: 62808.000021

[059] Figure 34 depicts mean dextromethorphan plasma concentrations following the administration of dextromethorphan hydrobromide in different formulations, doses and dosing regimens. [060] Figure 35 depicts plasma guaifenesin concentrations following the administration of 1200 mg guaifenesin along with 60 dextromethorphan hydrobromide in three different formulations. [061] Figure 36 depicts dextromethorphan plasma concentrations following the administration of 60 mg dextromethorphan hydrobromide at three different rates. [062] Figure 37 depicts plasma guaifenesin concentrations following the administration of 1200 mg guaifenesin and 60 mg dextromethorphan in an experimental formulation under fed and fasted conditions. [063] Figure 38 depicts plasma dextromethorphan concentrations following the administration of 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin in the fed and fasted conditions. [064] Figure 39 depicts steady-state plasma concentrations of guaifenesin following the multiple dose administration of 1200 mg guaifenesin in different formulations. [065] Figure 40 depicts mean steady-state guaifenesin plasma concentration-time profiles. [066] Figure 41 depicts steady-state plasma concentrations of dextromethorphan following the multiple dose administration of 60 mg dextromethorphan hydrobromide in different formulations and/or different dosage rates. [067] Figure 42 depicts dextromethorphan plasma concentrations following the administration of 60 mg dextromethorphan hydrobromide in different formulations and dosage rate. [068] Figure 43 depicts a process flow diagram for the manufacture of guaifenesin

DC (95%). [069] Figure 44 depicts a process flow diagram for a guaifenesin/pseudoephedrine product (1200/120 mg) tablets. [070] Figure 45 depicts a process flow diagram for guaifenesin/pseudoephedrine product (600/60 mg) tablets. Agent's File Reference: 62808.000021

DETAILED DESCRIPTION OF THE INVENTION

[071] The invention relates to sustained release formulations of guaifenesin. In a preferred embodiment, the formulations also comprise at least one additional drug in immediate release form, sustained release form, or both. Each formulation comprises a specific quantity of guaifenesin and may optionally contain at least one additional drug. The immediate release formulation is formulated to dissolve in aqueous acidic medium, such as that found in the stomach, to provide rapid release of the guaifenesin and optionally the at least one additional drug. In a preferred embodiment, the sustained release formulation comprises a combination of a hydrophilic polymer and a water- insoluble polymer in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to- one (4:1).

[072] In a preferred embodiment the hydrophilic polymers are selected from acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, methylcellulose, hydroxomethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxyrnethylcellulose, agar, pectin, carrageen, alginates, carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharides, and modified starch derivatives. In a more preferred embodiment the hydrophilic polymers are selected from cellulose ethers. In a most preferred embodiment the hydrophilic polymers are selected from hydroxypropyl methylcelluloses such as Methocel (E10M). Preferred total amounts of the hydrophilic polymer include more than 0.5% and less than 10% by weight for a 1200 mg tablet. More preferably hydrophilic polymer amounts includes more than 1.0% and less than 7.0%, more than 2% and less than 6.0%. These amounts include the hydrophilic polymer in the Guaifenesin DC described below. The hydrophilic polymer added separately to form the release-delaying matrix is preferably from about 0.5% to 4.0% and more preferably from about 1.0% to 2.0%. It should be recognized that these Agent's File Reference: 62808.000021

amounts may be proportionally present in a 600 mg tablet or any desired formulation strength.

[073] In a preferred embodiment the water-insoluble polymers are selected from polyacrylic acids, acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate. In a more preferred embodiment the water-insoluble polymers are selected from acrylic resins. In a most preferred embodiment the water-insoluble polymers are selected from Carbomer acrylic resins such as Carbomer 934P. Preferred amounts of the water-insoluble polymer include more than about 0.5% and less than about 2.5% by weight for a 1200 mg tablet. More preferably hydrophilic polymer amounts includes more than about .75% and less than about 1.5%, and most preferably more than about .9% and less than 1.25%. It should be recognized that these amounts may be proportionally present in a 600 mg tablet or any desired formulation strength.

[074] The invention also relates to sustained release preparations of the type described above in the form of bi-layered tablets or capsules having a combination of beads or granules of immediate release formulation and beads or granules of sustained release formulation. Alternatively, the sustained release formulation may comprise a core that is coated by a layer of immediate release formulation to form a single tablet. For purpose of illustration only, the invention will be described in detail in the context of the bi-layered tablet embodiment. When the embodiment is a bi-layered tablet, the tablet is made of two portions: one portion comprising a sustained release formulation and a second portion comprising an immediate release formulation. In a preferred embodiment, the at least one additional drug can be present within the sustained release formulation, the immediate release formulation, or both depending upon the desired effect.

[075] For instance, a preferred embodiment of the present invention has the following ingredients and proportions in the sustained release layer (mg/tablet): 1052.6 mg Guaifenesin DC (95%) [1000.0 mg of Guaifenesin, USP and 52.6 mg of hydroxypropyl methylcellulose, USP]; 120.0 mg Pseudoephedrine HCL, Agent's File Reference: 62808.000021

USP; 30.0 mg hydroxypropyl methylcellulose, USP [Methocel E10M, USP]; 15.0 mg Carbomer 934P, NF [Carbopol 974P]; 0.4 mg FD&C Red #40 Aluminum Lake (14-16%); and 10.0 mg magnesium stearate, NF for a total sustained release weight of 1228.0 mg. In a preferred embodiment the immediate release layer has the following proportions: 210.5 mg Guaifenesin DC (95%) [200.0 mg of guaifenesin, USP and 10.5 mg of hydroxypropyl methylcellulose, USP]; 117.5 mg of microcrystalline cellulose, NF [Avicel PH102]; 30.0 mg of sodium starch glycolate, NF [EXPLOTAB]; and 1.0 mg magnesium stearate, NF for a total immediate release weight of 359.0 mg. [076] In another preferred embodiment a 1200 mg Guaifenesin/120 mg Pseudoephedrine Tablet has the following ingredients and proportions:

' Based on batch size of 900,000 tablets

Guaifenesin direct compression used in the manufacturing process consists of 95% Guaifenesin, USP, 5% hydroxpropyl methylcellulose, USP (Methocel™ E10M) granulated with Purified water, USP (49.21 Kg). ³ Water is removed during processing of Guaifenesin DC 95%. Agent's File Reference: 62808.000021

[077] In another preferred embodiment a 600 mg Guaifenesin/60 mg Pseudoephedrine Tablet has the following ingredients and proportions:

¹ Based on batch size of 1,800,000 tablets

² guaifenesin direct compression used in the manufacturing process consists of 95% guaifenesin,

USP, 5% hydroxpropyl methylcellulose, USP (Methocel™ E10M) granulated with purified water,

USP (49.21 Kg). 3

Water is removed during processing of Guaifenesin DC 95%.

Agent's File Reference: 62808.000021

[078] In another example, a 1200 mg Guaifenesin/120 mg Pseudoephedrine Tablet may also have the following properties:

Description 1200 mg bi-layer tablet

Average Tablet Weight 1587.0 mg ± 3% (1539.4 mg - 1634.6 mg)

Tablet Thickness 0.321" - 0.341"

Tablet Hardness 25-45 SCU

Friability NMT 0.8%

Loss on Drying NMT 2.0%

(moisture) NMT 31.74 mg/unit dose

Assay-guaifenesin 1140.0 - 1260.0 mg/tablet (95.0 - 105.0%)

Assay-Pseudoephedrine 116.6 to 128.4 mg/tablet hydrochloride (93.0 - 107.0%)

Guaifenesin The retention time of the peak obtained from the Assay

Identification A preparation matches that of the Standard preparation.

Guaifenesin (Identification B) A deep-cherry red to purpose color is produced.

Pseudoephedrine hydrochloride The retention time of the peak obtained from the Assay

Identification A preparation matches that of the Standard preparation.

Pseudoephedrine hydrochloride The IR spectrum matches that of the standard in the 2510 cm^"'

Identification B to 2400 range cm^"'.

Dose Uniformity %RSD NMT 6.0% (%RSD NMT 7.8% for Level II) All individual values between 85.0 - 115.0%

(For Level II, one value is allowed outside 85.0 - 115.0%, but none outside 75.0 - 125.0%)

Dissolution: 1 Hour: NMT 45%

Guaifenesin 2 Hour: 36 - 56% 6 Hour: 61 - 81% 12 Hour: NLT 85%

Dissolution: 1 Hour: NMT 53%

Pseudoephedrine hydrochloride 2 Hour: 48 - 68% 6 Hour: NLT 75% 12 Hour: NLT 85% Agent's File Reference: 62808.000021

[079] In another example, a 600 mg Guaifenesin/60 mg Pseudoephedrine Tablet may also have the following properties:

Description 600 mg bi-layer tablet

Average Tablet Weight 794.1 mg ± 3% (766.4 mg - 821.8 mg)

Tablet Thickness 0.247" - 0.262"

Tablet Hardness 17 - 32 SCU

Friability NMT 0.8%

Loss on Drying NMT 2.0% (moisture) NMT 15.88 mg/unit dose

Assay-Guaifenesin 570.0 - 630.0 mg/tablet(95.0 - 105.0%)

Assay-Pseudoephedrine 58.2 to 61.8 mg/tablet hydrochloride (93.0 - 107.0%)

Guaifenesin The retention time of the peak obtained from the Assay Identification A preparation matches that of the Standard preparation.

Guaifenesin A deep-cherry red to purpose color is produced. Identification B

Pseudoephedrine hydrochloride The retention time of the peak obtained from the Assay Identification A preparation matches that of the Standard preparation.

Pseudoephedrine hydrochloride The IR spectrum matches that of the standard in the 2510 cm^"' Identification B to 2400 range cm^"1.

Dose Uniformity %RSD NMT 6.0% (%RSD NMT 7.8% for Level II)

All individual values between 85.0 - 115.0%

Dissolution: 1 Hour: NMT 48%

Guaifenesin 2 Hour: 41 - 61% 6 Hour: 73 - 93% 12 Hour: NLT 90%

Dissolution: l Hour: NMT 58%

Pseudoephedrine hydrochloride 2 Hour: 56 - 76% 6 Hour: NLT 80% 12 Hour: NLT 85%

[080] In one embodiment, the 1200/60 mg guaifenesin/dextromethorphan weight specification is 1530.4 mg ± 3.0%, corresponding to a range of 1484.5 - 1576.3 Agent's File Reference: 62808.000021

mg. For the 600/30 mg tablet, the weight specification is 765.2 mg ± 3.0%, corresponding to a range of 742.2 - 788.2 mg. This specification range of ± 3.0% of the theoretical weight is similar to the guaifenesin alone 1200 mg and 600 mg tablets, respectively.

[081] The proposed hardness and thickness specifications for the 1200/60 mg guaifenesin/dextromethorphan tablet are 15-65 SCU and 0.310" - 0.340", respectively. Tablets pressed at 527 tpm at the minimum hardness parameter (12LB86A) ranged from 0.329" - 0.334" and 17-23 SCU. The friability ranged from 0.20-0.33%. Tablets pressed at 737 tpm at the minimum hardness parameter (12LB86B) ranged from 0.331" - 0.335" and 15-24 SCU. The friability ranged from 0.20-0.39%. Dissolution testing was performed for each test condition (527 tpm and 737 tpm) within one hour of compression. No significant difference was seen in the release profile between the test samples and the pilot batches.

[082] Further tablets pressed as thin and as hard as the press would allow at speeds of 527 tpm (12LB86C) and 737 tpm (12LB86D) provided a thickness range of 0.303" - 0.312" with a corresponding initial hardness range of 39-47 SCU at 527 tpm. The friability ranged from 0.07-0.13%. A thickness range of 0.304" - 0.313" was obtained with a corresponding initial hardness range of 38-47 SCU at 737 tpm. The friability ranged from 0.06-0.13%. Historically, it has been noted that these tablets harden during the first few days after compression. Therefore, these 'hard' tablets were tested for dissolution at least 5 days after compression. The hardness range on the fifth day after compression was 52-60 SCU for the tablets pressed at 527 tpm. The hardness range on the fifth day after compression was 48-56 SCU for the tablets pressed at 737 tpm. Again, the dissolution profile for the test samples corresponded closely with that seen in the pilot batches. Additionally, a tablet hardness range of 60-79 SCU was reported for PB01-H30 at the 3-month real-time stability time point. No significant difference in the dissolution profile from "T₀" was noted.

[083] The proposed hardness and thickness specifications for the 600/30 mg guaifenesin/dextromethorphan tablet were 15-65 SCU and 0.220" - 0.260" Agent's File Reference: 62808.000021

respectively. Tablets pressed at the minimum hardness parameter at 527 tpm (12LB85A) ranged from 0.257" - 0.260" and 8-13 SCU. The friability ranged from 0.13-0.26%. Tablets pressed at the minimum hardness parameter at 840 tpm (12LB85B) ranged from 0.258" - 0.261" and 8-13 SCU. The friability ranged from 0.13-0.26%. Dissolution testing was performed for each test condition (527 tpm and 840 tpm) within one hour of compression. No significant difference was seen in the release profile between the test samples and the pilot batches.

[084] Tablets were then pressed as thin and as hard as the press would allow. A range of 0.232" - 0.241" was obtained at compression with a corresponding hardness ranging from 25-30 SCU at 527 tpm (12LB85C). The friability ranged from 0.13-0.78%. The hardness on the seventh day after compression ranged from 28-34 SCU. A range of 0.230" - 0.241" was obtained at compression with a corresponding hardness ranging from 23-30 SCU at 840 tpm (12LB85D). The friability ranged from 0.00-0.13%. The hardness on the seventh day after compression ranged from 28-33 SCU. Again, the dissolution profile for the test samples (seven days after compression) corresponded closely with that seen in the pilot batches. Additionally, a tablet hardness range of 37-51 SCU was reported for lot PB01-H54 at the 3-month real-time stability time point. No significant difference in the dissolution profile from "To" was noted.

[085] The preferred 1200 mg guaifenesin/60 mg dextromethorphan tablets have an average tablet thickness of 0.305" - 0.335", an average tablet hardness of 25 - 35 SCU (in process), and average tablet hardness 20 - 79 SCU (at time of release).

[086] The preferred 600 mg guaifenesin/30 mg dextromethorphan tablets have an average tablet thickness of 0.230" - 0.260", an average tablet hardness of 20 - 30 SCU (in process), and an average tablet hardness of 10 - 51 SCU (at time of release through expiration date).

[087] The specification of NMT 0.8% set for the friability of both guaifenesin/dextromethorphan tablet strengths is based on the limit established with the guaifenesin alone tablets. The specification for Loss on Drying is Agent's File Reference: 62808.000021

comparable to guaifenesin alone, i.e. NMT 2.0%. The moisture limit is 2.0% of the total theoretical tablet weight, recorded in mg/unit dose.

[088] The range for the specification for guaifenesin is based on the labeled amount, 1200 mg or 600 mg ± 4.0%. For the 1200/60 mg guaifenesin/dextromethorphan tablet, the range is 1152.0 - 1248.0 mg per tablet. For the 600/30 mg guaifenesin/dextromethorphan tablet, the range is 576.0 - 624.0 mg per tablet. The range for the specification for dextromethorphan HBr is based on the labeled amount, 60 mg or 30 mg ± 4.0%. For the 1200/60 mg tablet, the range is 57.6 - 62.4 mg per tablet. For the 600/30 mg tablet, the range is 28.8 - 31.2 mg per tablet.

[089] Other embodiments of the invention, include a SCU that is preferably less than 43, more preferably less than 41, more preferably less than 38, , more preferably less than 37, and more preferably between 32 and 35. SCU is also preferably greater than 21, more preferably greater than 24, more preferably greater than 28, and more preferably greater than 31.

[090] The weight of 10 bi-layer guaifenesin/pseudoephedrine tablets (1200 mg/120 mg) is preferably less than 16.4g, more preferably less than 16.35g, more preferably less than 16.29g, more preferably less than 16.22g, more preferably less than 16.16g, more preferably less than 16.10g, more preferably less than 16.04g, and more preferably between 15.71g and 16.03g. The weight of 10 bi- layer tablets is also preferably greater than 15.35g, more preferably greater than 15.40g, more preferably greater than 15.46g, more preferably greater than 15.53g, more preferably greater than 15.59g, more preferably greater than 15.65g.

[091] Other embodiments and characteristics of the invention are described in further detail below.

Sustained Release Formulation

[092] In one embodiment of the invention, a sustained release formulation comprises guaifenesin and optionally at least one drug both mixed with a polymer blend which comprises at least one hydrophilic polymer and at least one water-insoluble polymer. In a further embodiment, the sustained release Agent's File Reference: 62808.000021

formulation may comprise a combination of guaifenesin and at least one additional drug, wherein the additional drug may be selected from, but is not limited to, an antitussive such as dextromethorphan hydrobromide, codeine, hydrocodone, a decongestant such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride or ephedrine, an antihistamine such as chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, and clemastine fumerate, an analgesic such as aspirin, ibuprofen, naprosin, and acetaminophen, or . combinations thereof. Preferably, the drug is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

[093] The sustained release matrix utilizes polymers as described below to achieve the required delay release profile in vivo. To obtain the release profile proper mixing and formulation is required. For instance, too much hydrophilic polymer will result in too quick of a release and not allow for 12 hour relief while too much hydrophobic polymer will result in inadequate C_maχ for relief of symptoms. Therefore, the selection of polymers, the amounts utilized in total and the amount utilized in comparison to each other provide a matrix which is then formulated according to the below methods to provide the appropriate release profile.

[094] Hydrophilic polymers suitable for use in the sustained release formulation include: one or more natural or partially or totally synthetic hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, modified cellulosic substances such as methylcellulose, hydroxomethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose; proteinaceous substances such as agar, pectin, carrageen, and alginates; and other hydrophilic polymers such as carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives, and other hydrophilic polymers known to those of skill in the art or a combination of such polymers. Agent's File Reference: 62808.000021

[095] These hydrophilic polymers gel and dissolve slowly in aqueous acidic media thereby allowing the guaifenesin and at least one drug to diffuse from the gel in the stomach. When the gel reaches the intestines, where the guaifenesin and the drug are fairly absorbable, it dissolves in controlled quantities in the higher pH medium to allow sustained release of guaifenesin and at least one drug throughout the digestive tract. Preferred hydrophilic polymers are the hydroxypropyl methylcelluloses such as those manufactured by The Dow Chemical Company and known as Methocel ethers. In one preferred embodiment of a sustained release formulation the hydrophilic polymer is a Methocel ether known as Methocel E10M.

[096] Water-insoluble polymers, which are suitable for use in the sustained release formulation, are polymers which generally do not dissolve in solutions of a pH below 5, and dissolve more slowly in basic solutions than the hydrophilic polymer. Because the polymer is insoluble in low pH environments such as those found in gastric fluid, it aids in retarding drug release in those regions. Likewise, because the polymer dissolves more slowly in solutions of higher pH than hydrophilic polymers, it aids in retarding drug release throughout the intestines. This overall delayed release results in a more uniform serum concentration of guaifenesin.

[097] The water-insoluble polymers suitable for use in this invention include for example: polyacrylic acids, acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and other polymers common to those of skill in the art. In a preferred embodiment, a sustained release formulation comprises the acrylic resin Carbopol 974P supplied by BF Goodrich.

[098] A sustained release formulation of invention may further comprise pharmaceutical additives including, but not limited to: lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, and mineral oil; colorants; binders such as sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone polyethylene glycol, Pullulan and corn syrup; glidants such Agent's File Reference: 62808.000021

as colloidal silicon dioxide and talc; surface active agents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol, and quarternary ammonium salts; preservatives and stabilizers; excipients such as lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, chloride, sulfate and phosphate salts of potassium, sodium, and magnesium; and/or any other pharmaceutical additives known to those of skill in the art. Colorants include, but are not limited to, Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, or FD&C Blue No. 1 and other various certified color additives (See 21 CFR, Part 74). h one preferred embodiment, a sustained release formulation further comprises magnesium stearate and Emerald Green Lake. In another preferred embodiment, a sustained release formulation further comprises magnesium stearate and FD&C Blue No. 1 Aluminum Lake Dye. [099] h another embodiment the modified release formulation comprises at least two drugs, one of which is guaifenesin, at least one hydrophilic polymer, at least one water-insoluble polymer, and at least one pharmaceutical additive which permits dissolution of drugs in a therapeutically effective profile for an extended period of time. It is preferred that the drug profile provides a therapeutically effective profile for greater than 10 hours, more preferably greater than 12 hours, and most preferably greater than 14 hours, hi a preferred embodiment, a modified release formulation comprises from about 75% to about 95% guaifenesin by weight, from about 1% to about 15% by weight of an additional drug, from about 0.5% to about 10% hydroxypropyl methylcellulose, from about 0.5% to about 2.5% acrylic resin, from about 0.4% to about 1.5% magnesium stearate, and from about 0.01% to about 1% colorant by weight. In a more preferred embodiment, a modified release formulation comprises from about 75% to about 80% guaifenesin by weight, from about 3% to about 10% by weight of an additional drug, from about 3% to about 6% hydroxypropyl methylcellulose, from about 1% to about 1.5% acrylic resin, from about 0.7% to about 1% magnesium stearate, and from about 0.03% to about 0.13% colorant by weight. Agent's File Reference: 62808.000021

[0100] The sustained release formulation controls the release of guaifenesin and optionally at least one additional drug into the digestive tract over an extended period of time resulting in an improved profile when compared to immediate release combinations, guaifenesin solubility is effected by the pH of the environment in which it is present (i.e. stomach versus intestinal tract). In a more acidic environment, such as the stomach, guaifenesin is less soluble while in a higher pH environment, such as the intestines, guaifenesin is readily soluble. The pH changes throughout the digestive tract effect the dissolution rate of guaifenesin and are partially determinate of the concentrations of guaifenesin attained in the blood and tissues.

[0101] To maintain a blood concentration of guaifenesin which provides good therapeutic effect, the release, or dissolution, of guaifenesin from a formulation matrix is preferably retarded and/or controlled through the intestines. The hydrophilic and water-insoluble polymers of the sustained release formulation gel when exposed to media of low pH. This gel matrix allows the sustained release drugs, e.g. guaifenesin alone or in combination with a second drug to diffuse at a controlled rate when exposed to a higher pH environment.

[0102] When using drugs approved by the Food and Drug Administration (FDA), the sustained release formulation may be formulated to mimic the blood serum profile of guaifenesin and optionally the additional drug(s) as described in the clinical documents filed with the FDA or as required by the FDA. In other words, the sustained release formulation releases at least one additional drug at a similar rate to the commercially available formulation, thereby providing a therapeutically effective amount of the additional drug.

[0103] In a preferred embodiment, a sustained release formulation comprises a hydrophilic polymer and a water-insoluble polymer in a ratio of about one-to- one (1:1) to about nine-to-one (9:1), more preferably the range is about three-to- two (3:2) to about six-to-one (6:1), and most preferably the range of hydrophilic polymer to water-insoluble polymer is about two-to-one (2:1) to about four-to- one (4:1). In another embodiment, the sustained release formulation comprises not more than about 10% hydrophilic polymer, preferably, not more than 6%, Agent's File Reference: 62808.000021

and in a more preferred embodiment, the sustained release formulation also comprises not more than 2.5% of the water-insoluble polymer by weight. In another preferred embodiment, the water- hydrophilic polymer is hydroxypropyl methylcellulose and the water-insoluble polymer is acrylic resin. The ratios result in a serum concentration profile of guaifenesin that provides an optimal therapeutic concentration for about twelve hours.

[0104] A sustained release formulation may be manufactured according to any appropriate method known to those of skill in the art of pharmaceutical manufacture. In one embodiment, guaifenesin and a hydrophilic polymer may be mixed in a mixer with an aliquot of water to form a wet granulation. The granulation may be dried to obtain hydrophilic polymer encapsulated granules of guaifenesin. The resulting granulation may be milled, screened, and then blended with various pharmaceutical additives, water insoluble polymer, and additional hydrophilic polymer. The formulation may then tableted and may further be film coated with a protective coating which rapidly dissolves or disperses in gastric juices.

[0105] In a preferred embodiment the method of preparing a sustained release formulation comprises loading approximately 126 kg of guaifenesin and about 2 kg of Methocel E10M into a high shear mixer. The Methocel E10M and guaifenesin may be mixed for about seven minutes at a mixing speed of about 150 RPM and a chopper speed of about 2000 RPM. The mixing and chopping speeds may then be increased to about 200 RPM and 3000 RPM respectively for about five minutes while about 49 kg of water are added to the mixer contents. The mixer may be run for two additional minutes to complete granulation. In a further preferred embodiment, the shut off for the mixer load is set to 21 kilowatts.

[0106] The wet granulation may be emptied into a fluid bed bowl and placed into a fluid bed dryer set to a dryer air flow of 900 CFM and an inlet temperature of about 50°C to about 55°C until the outlet temperature increases at a rate of 1°C per minute. The air flow may then be decreased to 600 CFM, and the inlet temperature may be decreased to 43°C until the granulation is dried to a moisture Agent's File Reference: 62808.000021

content of no more than 0.5%. In another preferred embodiment, the outlet temperature is set to a cut-off of 48°C. In yet another preferred embodiment, an agitator in the fluid bed bowl may be run intermittently during drying. The dried granulation may be passed through a mill fitted with a suitable screen size so that not more than about 30% of the resulting granulation comes through a 100 mesh screen and not more than about 10% of the resulting granulation is retained on a 10 mesh screen. In one preferred embodiment, the dried granulation may be passed through a mill fitted with a 0.109" size screen at a mill speed of about 500 to about 1500 RPM and a screw feed rate of about 35 to about 45 RPM. The resulting screened granulation is about 95% guaifenesin and is called G Guaifenesin DC (Direct Compressed) herein after. Screened granulation may be transferred to a 10 cubic foot N blender, combined with about another 0.6 kg of Methocel E10M, about 0.3 kg of a colorant such as Emerald Green Lake or FD&C BLUE No. 1, about 0.7 kg of magnesium stearate, and about 1.3 kg of Carbopol 974P. The combination may be blended for about three minutes.

[0107] In another preferred embodiment the method of preparing a sustained release formulation comprises loading about 101 kg to about 150 kg of guaifenesin, about 4.5 kg to about 18 kg of the additional drug, about 4.5 kg to about 5 kg of Methocel E10M, about 1.5 kg to about 2.25 kg of Carbopol® 974P, and about 40 g to about 240 g of colorant into a high shear mixer. If at this time water is to be added, then about 1 kg to about 1.5 kg of magnesium stearate is added as well. The ingredients may be mixed for about ten to about 12 minutes at a mixing speed of about 150 RPM and a chopper speed of about 2000 RPM. The mixing and chopping speeds may then be increased to about 200 RPM and 3000 RPM, respectively, for about five minutes while optionally about 29 kg of water are added to the mixer contents. If no water is added, then from about 1 kg to about 1.5 kg of magnesium stearate can be added at this time. The mixer may be run for ten additional minutes to complete granulation. In a further preferred embodiment, the shut off for the mixer load is set to 21 kilowatts.

[0108] The wet granulation may be emptied into a fluid bed bowl and placed into a fluid bed dryer set to a dryer air flow of 900 CFM and an inlet temperature of Agent's File Reference: 62808.000021

about 38°C to about 48°C until the outlet temperature increases at a rate of 1°C per minute. The air flow may then be decreased to 600 CFM, and the inlet temperature may be decreased to 43 °C until the granulation is dried to a moisture content of no more than 0.5%. In another preferred embodiment, the outlet temperature is set to a cut-off of 48°C. In yet another preferred embodiment, an agitator in the fluid bed bowl may be run intermittently during drying. The dried granulation may be passed through a mill fitted with a suitable screen size so that not more than about 30% of the resulting granulation comes through a 100 mesh screen and not more than about 10% of the resulting granulation is retained on a 10 mesh screen, h one preferred embodiment, the dried granulation may be passed through a mill fitted with a size screen of about 0.109" to about 0.125" at a mill speed of about 500 to about 1500 RPM and a screw feed rate of about 35 to about 45 RPM.

[0109] The resulting formulations may further be compressed on a tablet compressor machine using tooling to form tablets. The tablets may be any appropriate weight, size, and shape depending on the desired dosage strength of tablet. In one embodiment, these tablets may further be loaded into a coating pan and film coated with Opadry Y-S-3-714 (supplied by Colorcon, Inc.) and air dried in the pan.

[0110] In another embodiment, the method of preparing a sustained release formulation comprises blending the drugs, hydrophilic polymer, water insoluble polymer, and any pharmaceutical additives. The resulting blend may then be compressed into tablets and, if desired, film coated with a protective coating which rapidly dissolves or disperses in gastric juices. In a preferred embodiment of such a method, about 126 kg of Guaifenesin DC (about 95% purity), about 2.6 kg of Methocel E10M, about 1.3 kg of Carbopol 974P and about 0.333 kg of a colorant such as Emerald Green Lake or FD&C BLUE No. 1 may be loaded into a 10 cubic foot V Blender. The ingredients may be blended for about 20 minutes at which time about 0.6 kg of magnesium stearate may be added to the blended ingredients. This mixture may be blended for about another 10 minutes. The resulting formulation may further be compressed on a tablet compressor machine Agent's File Reference: 62808.000021

using tooling to form tablets. The tablets may be any appropriate weight, size, and shape depending on the desired dosage strength of the tablet. These tablets may further be loaded into a coating pan and film coated with Opadry Y-S-3-714 (supplied by Colorcon, Inc.) and air dried in the pan. 1] One embodiment of the invention uses the following general methods of manufacturing. To make the Guaifenesin DC (95%) intermediate granulation is conducted. The granulator is charged with purified water USP. The guaifenesin USP is added into the granulator. Next the hydroxypropyl methylcellulose USP (Methocel El OM) is added. The guaifenesin intermediate is dried with the air inlet temperature set about 5°C, until the air outlet temperature reached approximately 48°C. A sample may then be taken for in-process control testing (moisture analysis). After the material reaches the target moisture level, discharge the blend and proceed to milling. The dried granulation is then added to the milling machine and the milling process initiated. Again a sample may be taken for in-process control testing (moisture and sieve analysis). The milled material is collected into tared fiber drums, double-lined with plastic bags and containing a desiccant pouch between the inner and outer plastic bags, then transferred to blending. The batches are blended in a 60-cu. foot blender for at least 10 minutes. Again, a sample may be taken for in-process control testing (description, moisture, blend assay and sieve analysis). The final sieve analysis for milled Guaifenesin DC preferably will be as follows: not more than about 2 to 10% retained on a 10-mesh screen (2.00 mm), not less than about 50 to 60% retained on the 20-mesh through 100-mesh screens (150 μm), not less than about 4 to 6% will pass through a 100-mesh screen, and not more than about 15-20% will pass through a 140-mesh screen (106μm). When at least 50%, and preferably at least 60% of the Guaifenesin DC has a particle size in the range of from about 2 mm to about 150 μm, this facilitates both processability and achievement of the desired in vivo release profiles for the single entity and combination drugs described herein. The final Guaifenesin DC (95%) granulation is collected into tared fiber drums, double-lined with double-lined Agent's File Reference: 62808.000021

with plastic bags and containing a desiccant pouch between the inner and outer plastic bags.

[0112] In one embodiment the immediate release layer is produced according to the following general procedures. The released components, Guaifenesin DC (95%) and microcrystalline cellulose, NF (Avicel® PHI 02), are weighed and blended in a PK V-blender for about 20 minutes. Then sodium starch glycolate, NF (Explotab®), is added to the blender and blend for about 10 minutes. Next magnesium stearate, NF, is added to the blender and blended for approximately an additional 10 minutes. Sample may then be taken for in-process control testing (description, blend assay and sieve analysis).

[0113] In one embodiment the sustained release layer is produced according to the following general procedures. The released components, Guaifenesin DC (95%) and pseudoephedrine HCl, USP, previously screened through a No. 20 screen, are weighed and blended for ten minutes with hydroxypropyl methylcellulose, USP (Methocel E10M), Carbomer 934P and the appropriate colorant (FD & C Red No. 40 aluminum lake dye for 1200 mg guaifenesin 120 mg pseudoephedrine HCl tablets or FD & C Yellow No. 6 aluminum lake dye for 600 mg guaifenesin/60 mg pseudoephedrine HCl tablets). Next, an additional amount of Guaifenesin DC (95%), previously screened through a No. 10 screen, is added and blended for about ten minutes. Then magnesium stearate, NF, previously screened through a No. 20 screen, is added and blended for about ten minutes. Again, samples may be taken for in-process control testing (description, sieve analysis, and blend assay for both guaifenesin and pseudoephedrine HCl). Tablet Compression involved loading each blend (IR and SR) into its respective hopper on the bi-layer tablet compressor and then compressed according to the described parameters.

[0114] In another embodiment 1200 mg guaifenesin and 60 mg dextromethorphan HBr tablets are manufactured using the following protocol. The manufacturing process yields 600,000 tablets per batch for the 1200 mg guaifenesin and 60 mg dextromethorphan HBr or 1,200,000 tablets for 600 mg guaifenesin and 30 mg dextromethorphan HBr tablets. The components for the immediate release layer Agent's File Reference: 62808.000021

(IR layer) for both strength tablets are identical. The components for the sustained release layer (SR layer) for both strength tablets are also identical.

[0115] For the SR layer (for 1200 mg guaifenesin and 60 mg dextromethorphan HBr tablets), the guaifenesin and dextromethorphan HBr (previously screened through a 20-mesh screen), are granulated together with carbomer 934P, hydroxypropyl methylcellulose (Methocel E10M), and FD&C blue #1, aluminum lake (11 - 13%) using purified water as the granulating fluid in a Day mixer. The wet mass is evenly spread onto paper-lined trays and dried in a drying oven set at 109 ± 10° F for approximately 25 hours until the average moisture is not more than 1.5%. The process for the SR layer for 600 mg guaifenesin and 30 mg dextromethorphan HBr tablets is identical to the process for the 1200 mg guaifenesin and 60 mg dextromethorphan HBr extended release tablets with the exception of the dye used. The dye used in the half strength tablet is D&C yellow #10, aluminum lake (14 - 18%) while the dye in the full strength tablet is FD&C Blue #1, aluminum lake (11-13%). The dried granulation is milled using a Fitzpatrick Mill fitted with a 0.125" round-hole screen, knives forward at a "fast" speed. The granulation is fed into the mill using an automatic feeder. The six sublots (112.04 kg per sublot, granulated, dried, and milled as described above) are then blended together in a 60-cu. foot blender with magnesium stearate for ten minutes.

[0116] For the IR layer, the guaifenesin and dextromethorphan HBr (previously screened through a 20-mesh screen), are granulated together with sodium starch glycolate (Explotab), microcrystalline cellulose (Avicel PH102), and hydroxypropyl methylcellulose (Methocel E10M) using purified water as the granulating fluid in a Day mixer. The wet mass is evenly spread onto paper- lined trays and dried in a drying oven set at 109 ± 10° F for approximately 26 hours until the average moisture is not more than 2.0%. The IR layer process is the same for both tablet strengths. The dried granulation is passed through a Sweco equipped with 10-mesh screen. The granulation retained on the 10-mesh screen is milled using a Fitzpatrick Mill fitted with a 0.125" round-hole screen, knives forward at a "medium" speed. The granulation is fed into the mill using Agent's File Reference: 62808.000021

an automatic feeder. The milled material is later blended with the material that passed through the 10-mesh screen. The three sublots (95.52 kg per sublot, granulated, dried, and milled as described above) are then blended together in a 60 cu.-foot blender with magnesium stearate for ten minutes. Each blend is then loaded into their respective hoppers and compressed into bi-layer tablets.

[0117] Tablets comprising a sustained release formulation were prepared and tested for both in vitro and in vivo release characteristics as described in Examples 1, 2, and 3 below. In the in vitro testing, the dissolution rates of these tablets were compared against modified release tablets formulated without acrylic resin (Example 1), and three commercially available tablets, one being an immediate release formulation and the other two being modified release formulations. Tablets comprising the sustained release formulation demonstrated a slower, more controlled release of guaifenesin over a twelve hour period than any of the other tablets (see e.g., Example 1 and 2, and Figures 4 and 5).

[0118] In the in vivo testing, serum concentrations of subjects taking tablets comprising the sustained release formulation were compared with serum concentrations of subjects taking immediate release guaifenesin tablets and modified release guaifenesin tablets formulated without acrylic resin (see Example 3 and Figure 6). Tablets comprising the sustained release formulation demonstrated improved sustained release and therapeutic concentration over an extended time period compared to the other two formulations. Additionally, in the subjects taking tablets comprising the sustained release formulation, it took longer for guaifenesin to appear in the blood stream and the maximum guaifenesin serum concentration (C_max) was less than half that of the subjects who took the immediate release tablets.

Modified Release Formulation

[0119] To improve the C_maχ and guaifenesin appearance speed in patients while maintaining therapeutic effect for about twelve hours, a portion of a sustained release formulation as described above may be combined with a portion of an immediate release formulation in a modified release product. In a preferred embodiment, at least one additional drug can be present within the sustained Agent's File Reference: 62808.000021

release formulation, the immediate release formulation, or both depending upon the desired effect. When using drags approved by the Food and Drug Administration (FDA), the sustained release formulation, immediate release formulation, or both may be formulated to mimic the blood serum profile of the additional drug as described in the clinical documents filed with the FDA or as required by the FDA. In other words, the sustained and/or immediate release formulations of the modified release formulation may release the at least one additional drug at a similar rate to the commercially available formulation, thereby providing a therapeutically effective amount of the additional drug.

[0120] The modified release formulation can be in the form of bi-layered tablets, capsules having a combination of beads or granules of immediate release formulation and sustained release formulation, or a tablet wherein the sustained release formulation comprises a core that is coated by a layer of the immediate release formulation. For purpose of illustration only, the invention will be described in detail in the context of the bi-layered tablet embodiment.

[0121] The immediate release formulation may comprise guaifenesin and various pharmaceutical additives such as lubricants, colorants, binders, glidants, surface active agents, preservatives, stabilizers, as described above and/or any other pharmaceutical additives known to those of skill in the art. In one embodiment, the immediate release layer comprises at least one drug. In another embodiment, the immediate release layer comprises at least two drugs. In a more preferred embodiment, an immediate release formulation comprises guaifenesin, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. In another more preferred embodiment, an immediate release formulation comprises guaifenesin, at least one additional drug, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, and magnesium stearate. In yet another preferred embodiment, an immediate release formulation may comprise about 47% to about 58% guaifenesin, about 32% to about 42% microcrystalline cellulose, about 3% to about 8% sodium starch glycolate, and about 0.3% to about 0.5% magnesium stearate by weight. In yet another preferred embodiment, an immediate release formulation comprises about 47% Agent's File Reference: 62808.000021

to about 58% guaifenesin, about 3% to about 5% of at least one additional drug, about 32% to about 42% microcrystalline cellulose, about 2% to about 5% hydroxypropyl methylcellulose, about 3% to about 8% sodium starch glycolate, and about 0.3% to about 0.5% magnesium stearate by weight.

[0122] The bi-layer tablet may be manufactured according to any method known to those of skill in the art. The resulting tablet comprises the two portions compressed against one another so that the face of each portion is exposed as either the top or bottom of the tablet, or the resulting tablet may comprise the sustained release portion in the center coated by the immediate release portion so that only the immediate release portion is exposed. In a preferred embodiment, a bi-layer tablet comprises the two portions compressed against one another so that the face of each portion is exposed.

[0123] In a preferred method of manufacturing the bi-layer tablets, a sustained release formulation is prepared according to either a wet granulation or dry granulation method as described above. The immediate release formulation may be prepared by simply blending the guaifenesin with any pharmaceutical additives. If at least one additional drug is present, then water may be added to the formulation, as described above. In a further preferred embodiment, appropriate quantities of Guaifenesin DC, microcrystalline cellulose, and sodium starch glycolate are blended in a 10 cubic foot blender for about twenty minutes. An appropriate quantity of magnesium stearate is then added to the ingredients and blended for about ten more minutes to make an immediate release formulation. Portions of the sustained release formulation and immediate release formulation are then compressed by a tablet compressor machine capable of forming bi-layer tablets. In one embodiment, these tablets may further be coated with a protective film which rapidly disintegrated or dissolves in gastric juices.

[0124] The tablets may be made with any ratio of guaifenesin to at least one additional drug which results in a blood profile demonstrating appropriate therapeutic effect over extended time periods. As discussed above, the additional drug may be present in an amount sufficient to mimic the blood serum profile of the commercially available formulation of the drug and not to exceed Agent's File Reference: 62808.000021

the maximum dose approved by the FDA for the treatment, prevention, or amelioration of a particular illness or disease. In one embodiment, the ratio of total guaifenesin to at least one additional drug is about 1:1 to about 30:1, more preferably about 1:1 to 25:1, and more preferably about 20:1 by weight. Alternatively, the ratio is about 2:1 to about 15:1 by weight, and more preferably, the ratio of guaifenesin to at least one additional drug is about 8:1 to about 12:1 by weight. When present in the immediate release layer, the amount of the at least one additional drug should be sufficient to match the drug release profile of the additional drug within the sustained release profile.

[0125] In a preferred embodiment, the tablets are made with any ratio of guaifenesin to pseudoephedrine which results in a blood profile demonstrating appropriate therapeutic effect over extended time periods. As discussed above, the pseudoephedrine is present in an amount sufficient to mimic the blood serum profile of the commercially available formulation of the drug and not to exceed the maximum dose approved by the FDA for the treatment, prevention, or amelioration of a particular illness or disease. In one embodiment, the ratio of total guaifenesin to pseudoephedrine is about 1:1 to about 30:1, more preferably about 1:1 to 25:1, and more preferably about 20:1 by weight. Alternatively, the ratio of guaifenesin to pseudoephedrine is about 8:1 to about 12:1 by weight. In another embodiment the pseudoephedrine is only present in the immediate release layer.

[0126] In a preferred embodiment, the tablets are made with any ratio of guaifenesin to dextromethorphan which results in a blood profile demonstrating appropriate therapeutic effect over extended time periods. As discussed above, the dextromethorphan is present in an amount sufficient to mimic the blood serum profile of the commercially available formulation of the drug and not to exceed the maximum dose approved by the FDA for the treatment, prevention, or amelioration of a particular illness or disease. In one embodiment, the ratio of total guaifenesin to dextromethorphan is about 1:1 to about 30:1, more preferably about 1:1 to 25:1, and more preferably about 20:1 by weight. Agent's File Reference: 62808.000021

Alternatively, the ratio of guaifenesin to dextromethorphan is about 8:1 to about 12:1 by weight.

[0127] The tablets may be made with any ratio of sustained release to immediate release formulation which results in a blood profile demonstrating appropriate therapeutic effect over extended time periods. In one embodiment, the bi-layer tablets comprise guaifenesin distributed within the sustained release formulation and the immediate release formulation wherein the ratio of guaifenesin in the SR to guaifenesin in the IR is about 1:1 to about 20:1, more preferably about 1:1 to about 1:15 by weight, preferably the ratio is about 3:2 to about 11:1, and more preferably, the ratio of guaifenesin distributed within the sustained release formulation and the immediate release formulation is about 5:1 to about 9:1 by weight, respectively. For example, in a 1200 mg bi-layer modified release guaifenesin tablet, there may be about 200 mg of guaifenesin in the immediate release layer and about 1000 mg of guaifenesin in the sustained release layer.

[0128] The tablets may be made with at least one additional drug only within the sustained release formulation or with the additional drug only in the immediate release formulation. Optionally, the tablets may be made with at least one additional drug distributed within the sustained release formulation and the immediate release formulation. In one embodiment, the bi-layer tablets comprise an additional drag distributed within the sustained release formulation and immediate release formulation wherein the ratio of additional drug in the SR to additional drug in the IR is about 1:1 to about 20:1, more preferably about 1:1 to about 1:15 by weight, preferably the ratio is about 3:2 to about 9:1, and more preferably the ratio is about 3:1 to about 4:1 by weight, respectively. Alternatively the weight ratio for the additional drug is sustained release portion to immediate release portion is about 4:1 to about 1:1, more preferably about 1:1 to about 2:1.

[0129] In one preferred embodiment of manufacturing a 1200 mg bi-layer sustained release guaifenesin tablet, about 105 kg of Guaifenesin DC, about 2.5 kg of Methocel E10M, about 1.25 kg of Carbopol 974P, and about 0.333 kg of Emerald Green Lake or FD&C Blue No. 1 in a 10 cubic foot P.K. blender for Agent's File Reference: 62808.000021

about twenty minutes. About 0.6 kg of magnesium stearate may then be added and blending continued for about another ten minutes to prepare the sustained release formulation. Approximately 21 kg of Guaifenesin DC, approximately 11.75 kg of microcrystalline cellulose, and approximately 3 kg of sodium starch glycolate may be blended in a 3 cubic foot P.K. blender for about twenty minutes. Approximately 0.1 kg of magnesium stearate may then be added and blending continued for about another ten minutes to prepare the immediate release formulation. The two formulations may then be compressed to make bi- layer tablets wherein about 75% of each tablet may be sustained release formulation and about 25% of each tablet may be immediate release formulation. The tablets may be any dosage strength, size, or shape. In a preferred embodiment, 1200 mg tablets are round and about 5/8 inch in diameter, about 0.28 inch - 0.31 inch in thickness, weigh about 1.46 grams and have a hardness range of about 15-40 SCU. hi another preferred embodiment, 600 mg tablets are round and about 1/2 inch in diameter, about 0.218 inch - 0.230 inch in thickness, weigh about 0.729 grams and have a hardness range of about 12-30 SCU. [0130] In another preferred embodiment of manufacturing a 1200 mg bi-layer sustained release guaifenesin tablet, about 101 kg of Guaifenesin DC, about 4.5 kg of at least one additional drag such as dextromethorphan, about 5 kg of Methocel E10M, about 1.5 kg of Carbopol 974P, and about 0.04 kg of FD&C Blue No. 1 are blended in a 10 cubic foot Day mixer for about twelve minutes. Thereafter, about 29 kg of water is added and the mixture is blended for an additional 10 minutes, followed by drying. About 1 kg of magnesium stearate may then be added and blending continued for about another ten minutes to prepare the sustained release formulation. About 45.6 kg of GUAIFENESIN, about 3.6 kg of at least one additional drag such as dextromethorphan, about 40.32 kg of microcrystalline cellulose, and approximately 3 kg of sodium starch glycolate are blended in a 3 cubic foot Day mixer for about 12 minutes. Thereafter, about 36 kg of water is added and the mixture is blended for an additional 10 minutes, followed by drying. About 0.48 kg of magnesium stearate may then be added and blending continued for about another ten minutes Agent's File Reference: 62808.000021

to prepare the immediate release formulation. The two formulations may then be compressed to make bi-layer tablets wherein about 75% of each tablet may be sustained release formulation and about 25% of each tablet may be immediate release formulation. The tablets may be any dosage strength, size, or shape. In a preferred embodiment, 1200 mg tablets are round and about 5/8 inch in diameter, about 0.31 inch - 0.34 inch in thickness, weigh about 15.3 grams and have a hardness range of about 15-35 SCU. hi another preferred embodiment, 600 mg tablets are round and about 1/2 inch in diameter, about 0.22 inch - 0.26 inch in thickness, weigh about 7.65 grams and have a hardness range of about 15-65 SCU.

[0131] The immediate release portion of the bi-layer tablet is formulated to dissolve in aqueous media of low pH, such as that found in the stomach, to quickly release the guaifenesin contained within the portion. This results in rapid bioavailability of a high concentration of guaifenesin. As demonstrated in Example 6 and Figures 9 and 10 below, the immediate release portion of the bi- layer tablet results in a maximum serum concentration (C_maχ) and time of maximum serum concentration (T_ma ) equivalent to the C_max obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period.

[0132] The sustained release portion gels when exposed to media of low pH allowing the sustained release portion of the tablet to be passed into the intestinal tract. In the intestines, the gelled sustained release portion is exposed to a higher pH environment, causing the gel to slowly dissolve, thereby allowing guaifenesin to diffuse and dissolve out of the gelled matrix. This results in controlled bioavailability over an extended time period (i.e. eight to twelve or more hours) causing the tablet to provide extended therapeutic effect. As shown in Example 6 and Figures 9 and 10, the half-life of the modified release bi-layer tablet is increased to more than 3 hours and the tablet has an AUQ_nf (the area under a plasma concentration versus time curve from time 0 to infinity) of greater than 8000 hr-ng/mL. Agent's File Reference: 62808.000021

[0133] As demonstrated in Example 7 and Figure 11, the bi-layer tablets of the invention had a further surprising result in that a 600 mg tablet had a T_maχ equivalent to that of a 1200 mg and a C_maχ and AU _nf approximately half of a 1200 mg tablet. Thus, without adjusting or changing the composition of the sustained release formulation or bi-layer tablet, a lower dosage strength guaifenesin tablet of the invention exhibits a plasma concentration profile that is approximately directly proportional to that of a higher dosage strength guaifenesin tablet. As further demonstrated in Example 7 and Figure 11, the bi- layer tablets resulted in that the C_max and AUQ_nf of a 1200 mg tablet administered to volunteers who had been fasting and the C_maχ and AUCinf of a 1200 mg tablet administered to volunteers who had consumed a high fat meal were approximately equivalent. Thus, a bi-layer tablet of the invention demonstrates a reduced food effect, being approximately equally effective when administered to a patient on an empty or full stomach. Similar results were obtained for combination formulations for instance as described in Examples 8- 21.

[0134] Several combination formulations were also compared to commercial drags for bioavailability. For instance, Example 8 shows three batches of the 1200 mg guaifenesin/ 60 mg dextromethorphan HBr which were dissolved to determine the amount of dextromethorphan HBr released over time. Generally, the formulations had 1200 mg of guaifenesin and 60 mg dextromethorphan HBr and were studied over a 12 hour period. The released amount of dextromethorphan HBr was determined as a weight percent of dissolved dextromethorphan in contrast to the total weight of dextromethorphan prior to dissolution. After 1 hour about 46% to 47% of the dextromethorphan had dissolved. After 2 hours the about 59% to 60% had dissolved, after 6 hours 73% to 76% had dissolved, and after 12 hours about 86% to 89% by weight of the dextromethorphan had dissolved. Thus, the formulations of the invention reproducibly release dextromethorphan over time, (see, Figure 12). While, example 9, for instance demonstrates the in vivo bioavailability of a sustained release guaifenesin with dextromethorphan. Agent's File Reference: 62808.000021

[0135] Various combination guaifenesin/pseudoephedrine compositions were also examined to determine their dissolution rates and bioavailability. Examples 10 and 11, provide a formulations of guaifenesin and pseudoephedrine in the sustained release portion of a bi-layered tablet. Results demonstrated that combining the drugs into a single tablet according to methods of the invention did not effect their dissolution profile or their in vivo release profile.

[0136] The two prototype lots of example 12 showed similar in vitro release to market Mucinex™ and Sudafed®. In particular, Formulation B (lot PB01-K61) produced optimal bioavailability for both guaifenesin and pseudoephedrine and was therefore used in subsequent bioavailability studies.

[0137] Example 13 compared combination products for guaifenesin/ pseudoephedrine HCL) of 1200/120 mg strength, Formulation B(lot PB01- M65A2) and of 600/60 mg strength, Formulation C(lot PB01-A12A) to commercial Mucinex™ and Sudafed® 12 Hour. The 1200/120 mg strength showed bioequivalence for ratios of both C_maχ and AUQ_nf with a 90% confidence interval, which is contained in the 80-125% range. Further, the 600/60 mg strength demonstrated proportional dosage pharmacokinetics.

[0138] Example 14 compared reference Mucinex™ and Sudafed® 12 Hour to a 1200/120 mg strength test formulation (lot PB01-M65A3) for steady-state bioavailability in an 11 day twice-daily dose regime. The test formulation was bioequivalent (within the 80-125% range with a 90% confidence interval) when compared to the reference formulation. Therefore, for both guaifenesin and pseudoephedrine, the steady state for C_maχ and AUC_SS were bioequivalent.

[0139] Examples 15 and 17 compared the effect of a high fat meal for both reference formulations and combination formulations of the invention. The test formulation (lot PB01-M65) was not bioequivalent with regard to C_maχ for guaifenesin but was for the pseudoephedrine portion when compared to the reference. However, the AUQnf was bioequivalent for both guaifenesin and pseudoephedrine within the 80-125% range.

[0140] Example 16 compared single-dose relative bioavailability and interaction potential of guaifenesin and pseudoephedrine administered as Mucinex™ and Agent's File Reference: 62808.000021

Sudafed® 12 Hour alone or in combination. The results demonstrate that the pharmacokinetics of guaifenesin and pseudoephedrine are unaffected with regard to both AUCi_nf and C_max in the presence or absence of one another (ratios within 80-125%). This further confirms the results of the other examples which demonstrate bioequivalence for the combination formulations of the invention.

[0141] Example 18 compared the bioavailability of guaifenesin and dextromethorphan from an experimental formulation containing both guaifenesin and dextromethorphan as compared to reference guaifenesin and dextromethorphan. The pharmacokinetics of guaifenesin and dextromethorphan were not affected by the presence of the other component and the pharmacokinetics of dextromethorphan were linear over the range studied.

[0142] Example 19 compared the relative bioavailability of guaifenesin and dextromethorphan from an experimental formulation, containing both guaifenesin and dextromethorphan, as compared to reference guaifenesin and dextromethorphan. The guaifenesin in the experimental tablet was clearly bioequivalent to that of the Reference, Mucinex, in terms of C_maχ, AUCo_-t or AUCj_nf. Dextromethorphan hydrobromide in the experimental tablet was also found to be bioequivalent to both 30 mg dextromethorphan hydrobromide every 6 hours, and 20 mg every 4 hours, in terms of C_maχ, AUC₀-t or AUQ_nf.

[0143] Example 20 compared the relative bioavailability of guaifenesin and dextromethorphan from an experimental formulation containing both guaifenesin and dextromethorphan following the consumption of a high fat meal as compared to following an overnight fast. There was no food effect on the absorption of guaifenesin from the experimental tablet. There was an effect of food on the rate of absorption of dextromethorphan from the experimental tablet formulation (a small increase in the rate of absorption) but not on the extent of absorption.

[0144] Example 21 compared the relative bioavailability of guaifenesin and dextromethorphan from an experimental formulation containing both guaifenesin and dextromethorphan, as compared to reference guaifenesin and dextromethorphan products. The guaifenesin in the experimental tablet was Agent's File Reference: 62808.000021

bioequivalent to that of the Reference, Mucinex, in terms of C_maχ and AUC_SS within 80% to 125%. Dextromethorphan hydrobromide in the experimental tablet was bioequivalent to both 30 mg dextromethorphan hydrobromide every 6 hours, and 20 mg every 4 hours, in terms of C_max and AUC_SS within 80% to 125%.

[0145] These studies demonstrate the compositions of the invention provide systemic levels of drug over a 12-hour period. Additionally, the studies demonstrate the bioequivalence of the combination formulations. Comparison to FDA Approved Drugs

[0146] When using drugs approved by the Food and Drag Administration (FDA), the sustained release formulation alone or in combination with an immediate release component may be formulated to mimic the blood serum profile of guaifenesin and optionally the additional drug(s) as described in the clinical documents filed with the FDA or as required by the FDA. This information may be found at http://www.fda.gov/cder/foi/nda/2002/21-282_Mucinex.htm which is hereby incorporated by reference in its entirety. For instance, a single dose 400 mg immediate release tablet has a C_maχ of 2,463 ± 1033, a T_max of .5, an AUC_0-12 8,382 ± 3,282, an AUQ_nf 8,529 ± 3,362, and a T_1/2 of 0.78 ± 0.09. Alternatively, multiple doses of a 400 mg immediate release tablet has a C_max of 2,278 ± 791, a Tm_ax of .5, an AUC_0-12 7,751 ± 2,697, Cmi_n0 112 ± 52, and a C_mini2 137 ± 98. Preferably, the formulations result in a maximum serum concentration (C_max) and/or time of maximum serum concentration (T_maχ) equivalent to the C_maχ obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period. In other words, the sustained release formulation releases both the guaifenesin and at least one additional drug at a similar rate to the commercially available formulation, thereby providing a therapeutically effective amount of both drugs. Alternatively, the parameters may be calculated through any of the following or combinations thereof: C_max, C_mi_n, T_max, AUC;_nf, AUCo-_t, AUC_SS and Ti ₂. Unless otherwise specified, all reference to AUC_0-t in the specification and claims shall refer to data which corresponds to a time (t) of Agent's File Reference: 62808.000021

24 hours. The parameters may also be calculated from in vivo studies such as those presented herein where equivalence is determined from the mean and an 80-125% range with a 90% confidence level and/or one standard deviation from the mean. Alternatively, the parameters may also be calculated from in vivo studies such as those presented herein where equivalence is determined from the median and an 80-125% range with a 90% confidence level and/or one standard deviation from the median. Due to the extreme variability for dextromethorphan, as recognized by the FDA and the inherent variability of measuring plasma serum levels at the picogram level the equivalence is determined from the mean and a 50-150% range, more preferably the equivalence is determined from the mean and a 60-140% range, and most preferably the equivalence is determined from the mean and a 80-125% range with a 90% confidence level. Figures 31 and 32 demonstrate specification ranges for various batch compositions of the invention. 7] Additionally the C_maχ for either guaifenesin, the additional drag(s) or both is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the C_maχ for guaifenesin is preferably greater than 640 ng/mL, more preferably 700 ng/mL, more preferably 800 ng/mL, more preferably 900 ng/mL, more preferably 1000 ng/mL, more preferably 1100 ng/mL, and most preferably 1250 ng/mL depending on the formulation. The high end of the C_maχ for guaifenesin is preferably less than 3750 ng/mL, more preferably 3500 ng/mL, more preferably 3250 ng/mL, more preferably 3000 ng/mL, more preferably 2750 ng/mL, and most preferably 2500 ng/mL depending on the formulation. For a 1200 mg tablet the range is preferably between 1000 ng/mL and 3750 ng/mL, 1200 ng/mL and 3500 ng/mL, 1350 ng/mL and 3000 ng/mL, and 1450 ng/mL and 2750 ng/mL. For a 600 mg tablet the range is preferably between 320 ng/mL and 1875 ng/mL, 400 ng/mL and 1500 ng/mL, 500 ng/mL and 1375 ng/mL, and 625 ng/mL and 1250 ng/mL. Agent's File Reference: 62808.000021

[0148] Alternatively, the low end of the C_maχ for pseudoephedrine is preferably greater than 150 ng/mL, more preferably 175 ng/mL, more preferably 200 ng/mL, and most preferably 250 ng/mL depending on the formulation. The high end of the C_max for pseudoephedrine is preferably less than 500 ng/mL, more preferably 450 ng/mL, more preferably 400 ng/mL, and most preferably 375 ng/mL depending on the formulation. For a 120 mg tablet the range is preferably between 150 ng/mL and 500 ng/mL, 175 ng/mL and 500 ng/mL, 200 ng/mL and 450 ng/mL, 250 ng/mL and 400 ng/mL, and 300 ng/mL and 375 ng mL. For a 60 mg tablet the range is preferably between 75 ng/mL and 250 ng/mL, 88 ng/mL and 250 ng/mL, 100 ng/mL and 225 ng/mL, 125 ng/mL and 200 ng/mL, and 150 ng/mL and 188 ng/mL.

[0149] Alternatively, the low end of the C_maχ for dextromethorphan is preferably greater than 3840 pg/mL, more preferably 5,500 pg/mL, more preferably 6,600 pg/mL, more preferably 7,000 pg/mL, more preferably 7,700 pg/mL, more preferably 8,000 pg/mL, more preferably 8,800 pg/mL, more preferably 9,900 pg/mL, and most preferably 10,000 pg/mL depending on the formulation. The high end of the C_maχ for dextromethorphan is preferably less than 22,500 pg/mL, more preferably 16,500 pg/mL, more preferably 15,400 pg/mL, more preferably 14,300 pg/mL, more preferably 13,200 pg/mL, and most preferably 12,100 pg/mL depending on the formulation. For a 60 mg tablet the range is preferably between 9,600 pg/mL and 15,000 pg/mL, 10,800 pg/mL and 13,500 pg/mL, 10,800 pg/mL and 12,000 pg/mL, and 12,000 pg/mL and 13,500 pg/mL. For a 30 mg tablet the range is preferably between 7,200 pg/mL and 11,250 pg/mL, 8,100 pg/mL and 10,125 pg/mL, 8,100 pg/mL and 9,000 pg/mL, and 9,000 pg/mL and 10,125 pg/mL. In an alternative embodiment the low end of the C_max for dextromethorphan is preferably greater than 1300 pg/mL, more preferably 1,550 pg/mL, more preferably 1,860 pg/mL, more preferably 2,170 pg/mL, more preferably 2,480 pg/mL, and most preferably 2,790 pg/mL depending on the formulation. The high end of the C_max for dextromethorphan is preferably less than 5,400 pg/mL, more preferably 4,650 pg/mL, more preferably 4,350 pg/mL, Agent's File Reference: 62808.000021

more preferably 4,000 pg/mL, more preferably 3,750 pg/mL, and most preferably 3,400 pg/mL depending on the formulation.

[0150] The Cmi_n is another aspect which is often not met by various extended release drugs found on the market. Formulations of the invention provide a C_mj_n which maintains it therapeutic effectiveness for a period of at least 10 hours, more preferably 12 hours and most preferably 14 or more hours. Additionally the C_mi_n for either guaifenesin, the additional drug(s) or both is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the C_mi_n for guaifenesin is preferably greater than 40 ng/mL, more preferably 50 ng/mL, more preferably 60 ng/mL, and most preferably 70 ng/mL depending on the formulation. The high end of the C_mj_n for guaifenesin is preferably less than 200 ng/mL, more preferably 175 ng/mL, more preferably 150 ng/mL, and most preferably 125 ng/mL depending on the formulation. The C_min range for either a 1200 or a 600 mg tablet may be selected from 50 ng/mL and 150 ng/mL, 50 ng/mL and 125 ng/mL, 60 ng/mL, 125 ng/mL, 70 ng/mL and 125 ng/mL, 80 ng/mL and 125 ng/mL, between 35 ng/mL and 75 ng/mL, 40 ng/mL and 70 ng/mL, 45 ng/mL and 65 ng/mL, and 50 ng/mL and 60 ng/mL.

[0151] Alternatively, the low end of the C_mi_n for pseudoephedrine is preferably greater than 75 ng/mL, more preferably 100 ng/mL, more preferably 125 ng/mL, and most preferably 150 ng/mL depending on the formulation. The high end of the C_mi_n for pseudoephedrine is preferably less than 300 ng/mL, more preferably 250 ng/mL, more preferably 225 ng/mL, and most preferably 200 ng/mL depending on the formulation. The C_min range for either a 120 mg or 60 mg tablet may be selected from 75 ng/mL and 300 ng/mL, 100 ng/mL and 250 ng/mL, 125 ng/mL and 225 ng/mL, 150 ng/mL and 200 ng/mL.

[0152] Alternatively, the low end of the C_mi_n for dextromethorphan is preferably greater than 1,250 pg/mL, more preferably 1,500 pg/mL, more preferably 1,700 Agent's File Reference: 62808.000021

pg/mL, more preferably 2,000 pg/mL, and most preferably 2,250 pg/mL. Alternatively, the high end of the C_mi_n for dextromethorphan is preferably less than 3,750 pg/mL, more preferably 3,500 pg/mL, more preferably 3,250 pg/mL, more preferably 3,000 pg/mL, and most preferably 2,750 pg/mL depending on the formulation. Alternatively, the C_mi_n range for a 60 mg tablet may be selected from 7,200 pg/mL and 11,250 pg/mL, 8,100 pg/mL and 10,125 pg/mL, 8,100 pg/mL and 9,000 pg/mL, and 9,000 pg/mL and 10,125 pg/mL. The C_mi_n range for a 30 mg tablet may be selected from 5,400 pg/mL and 8,400 pg/mL, 6,075 pg/mL and 7,600 pg/mL, 6,075 pg/mL and 6,750 pg/mL, and 6,750 pg/mL and 7,600 pg/mL. In another embodiment the low end of the C_mi_n for. dextromethorphan is preferably greater than 1,050 pg/mL, more preferably 1,250 pg/mL, more preferably 1,450 pg/mL, more preferably 1,650 pg/mL, and most preferably 1,850 pg/mL. The high end of the C_mj„ for dextromethorphan is preferably less than 3,150 pg/mL, more preferably 2,950 pg/mL, more preferably 2,700 pg/mL, more preferably 2,500 pg/mL, and most preferably 2,300 pg/mL depending on the formulation. [0153] Formulations of the invention provide a T_max for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the T_maχ for guaifenesin is preferably greater than 0.6 hours, more preferably 0.8 hours, more preferably 0.9 hours, more preferably 1.0 hours, and most preferably 1.1 hours depending on the formulation. The high end of the T_ma for guaifenesin is preferably less than 3.0 hours, more preferably 2.5 hours, more preferably 2.25 hours, and most preferably 2 hours depending on the formulation. The T_maχ range may also be selected from between 0.6 hours and 3.0 hours, 0.8 hours and 2.5 hours, 0.9 hours and 2.25 hours, 1.0 hours and 2 hours, and 1.1 hours and 2 hours. Agent's File Reference: 62808.000021

[0154] Alternatively, the low end of the T_maχ for pseudoephedrine is preferably greater than 3.75 hours, more preferably 4.0 hours, more preferably 4.25 hours, more preferably 4.5 hours, and most preferably 4.75 hours depending on the formulation. The high end of the T_max for pseudoephedrine is preferably less than 9.0 hours, more preferably 8.5 hours, more preferably 8.0 hours, and most preferably 7.5 hours depending on the formulation. The T_max range may also be selected from between 3.75 hours and 9.0 hours, 4.0 hours and 8.5 hours, 4.25 hours and 8.0 hours, 4.5 hours and 7.5 hours, and 4.75 hours and 7.5 hours.

[0155] Alternatively, the low end of the T_{m x} for dextromethorphan is preferably greater than 3.3 hours, more preferably 3.9 hours, more preferably 4.6 hours, more preferably 5.2 hours, and most preferably 5.85 hours depending on the formulation. The high end of the T_maχ for dextromethorphan is preferably less than 10.6 hours, more preferably 9.8 hours, more preferably 9.1 hours, more preferably 8.8 hours, more preferably 8.5 hours, more preferably 7.8 hours and most preferably 7.2 hours depending on the formulation. The T_max range may also be selected from between 6.2 hours and 9.7 hours, 6.7 hours and 8.8 hours, 6.7 hours and 7.75 hours, and 7.75 hours and 8.8 hours for a 60 mg tablet. The T_max range may also be selected from between 4.6 hours and 7.25 hours, 5.2 hours and 6.5 hours, 5.2 hours and 5.8 hours, and 5.8 hours and 6.5 hours for a 30 mg tablet.

[0156] Formulations of the invention provide a AUC_lnf for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the AUQ_nf for guaifenesin is preferably greater than 4,000 hr- ng/mL, more preferably 5,000 hr-ng/mL, more preferably 5,500 hr-ng/mL, and most preferably 6,000 hr-ng/mL depending on the formulation. The high end of the AUCinf for guaifenesin is preferably less than 12,500 hr-ng/mL, more preferably 10,000 hr-ng/mL, more preferably 9,500 hr-ng/mL, and most Agent's File Reference: 62808.000021

preferably 9,000 hr-ng/mL depending on the formulation. For a 1200 mg tablet the AUQnf range may be selected from between 4,000 hr-ng/mL and 12,500 hr- ng/mL, 5,000 hr-ng/mL and 10,000 hr-ng/mL, 5,500 hr-ng/mL and 9,500 hr- ng/mL, and 6,000 hr-ng/mL and 9,000 hr-ng/mL. For a 600 mg tablet the AUQ_nf range may be selected from between 2,000 hr-ng/mL and 6,250 hr-ng/mL, 2,500 hr-ng/mL and 5,000 hr-ng/mL, 2,250 hr-ng/mL and 4,750 hr-ng/mL, and 3,000 hr-ng/mL and 4,500 hr-ng/mL.

[0157] Alternatively, the low end of the AUQ_nf for pseudoephedrine is preferably greater than 2,500 hr-ng/mL, more preferably 2,800 hr-ng/mL, more preferably 3,500 hr-ng/mL, and most preferably 3,750 hr-ng/mL depending on the formulation. The high end of the AUQ_nf for pseudoephedrine is preferably less than 6,000 hr-ng/mL, more preferably 5,800 hr-ng/mL, more preferably 5,500 hr-ng/mL, and most preferably 5,000 hr-ng/mL depending on the formulation. For a 120 mg tablet the AUC_mf may be selected from between 2,500 hr-ng/mL and 6,000 hr-ng/mL, 2,800 hr-ng/mL and 5,800 hr-ng/mL, 3,500 hr-ng/mL and 5,500 hr-ng/mL, and 3,750 hr-ng/mL and 5,000 hr-ng/mL. For a 60 mg tablet the AUCi_nf may be selected from between 1,250 hr-ng/mL and 3,000 hr-ng/mL, 1,400 hr-ng/mL and 2,900 hr-ng/mL, 1,750 hr-ng/mL and 2,750 hr-ng/mL, and 1,875 hr-ng/mL and 2,500 hr-ng/mL.

[0158] Alternatively, the low end of the AUQ_nf for dextromethorphan is preferably greater than 55,200 hr-ng/mL, more preferably 145,000 hr-ng/mL, more preferably 174,000 hr-ng/mL, more preferably 192,000 hr-ng/mL, more preferably 203,000 hr-ng/mL, more preferably 216,000 hr-ng/mL, more preferably 232,000 hr-ng/mL, more preferably 240,000 hr-ng/mL, and most preferably 261,000 hr-ng/mL depending on the formulation. The high end of the AUCinf for dextromethorphan is preferably less than 587,500 hr-ng/mL, more preferably 435,000 hr-ng/mL, more preferably 405,000 hr-ng/mL, more preferably 400,000 hr-ng/mL, more preferably 377,000 hr-ng/mL, more preferably 360,000 hr-ng/mL, more preferably 348,000 hr-ng/mL, and most preferably 320,000 hr-ng/mL depending on the formulation. For a 60 mg tablet the AUQnf may be selected from between 256,000 hr-ng/mL and 400,000 hr- Agent's File Reference: 62808.000021

ng/mL, 288,000 hr-ng/mL and 360,000 hr-ng/mL, 288,000 pg/mL and 320,000 hr-ng/mL, and 320,000 hr-ng/mL and 360,000 hr-ng/mL. For a 30 mg tablet the AUCin_f may be selected from between 192,000 hr-ng/mL and 300,000 hr-ng/mL, 216,000 hr-ng/mL and 270,000 hr-ng/mL, 216,000 hr-ng/mL and 240,000 hr- ng/mL, and 240,000 hr-ng/mL and 270,000 hr-ng/mL. In another embodiment the low end of the AUQ_nf for dextromethorphan is preferably greater than 15,000 hr-ng/mL, more preferably 18,000 hr-ng/mL, more preferably 21,000 hr- ng/mL, more preferably 24,000 hr-ng/mL, and most preferably 27,000 hr-ng/mL depending on the formulation. The high end of the AUCin_f for dextromethorphan is preferably less than 46,900 hr-ng/mL, more preferably 45,000 hr-ng/mL, more preferably 42,000 hr-ng/mL, more preferably 39,000 hr-ng/mL, more preferably 36,000 hr-ng/mL, and most preferably 33,000 hr-ng/mL depending on the formulation. 9] Formulations of the invention provide a AUC_0-t for either guaifenesin, the additional drag(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the AUCo-_t for guaifenesin is preferably greater than 3,200 hr- ng/mL, more preferably 3,700 hr-ng/mL, more preferably 4,000 hr-ng/mL, and most preferably 4,500 hr-ng/mL depending on the formulation. The high end of the AUCo-t for guaifenesin is preferably less than 11,250 hr-ng/mL, more preferably 10,500 hr-ng/mL, more preferably 9,500 hr-ng/mL, more preferably 9,000 hr-ng/mL, and most preferably 8,500 hr-ng/mL depending on the formulation. For a 1200 mg tablet the AUC₀._t may be selected from between 3,200 hr-ng/mL and 11,250 hr-ng/mL, 3,700 hr-ng/mL and 10,500 hr-ng/mL, 4,000 hr-ng/mL and 9,500 hr-ng/mL, 4,250 hr-ng/mL and 9,000 hr-ng/mL, and 4,500 hr-ng/mL and 8,500 hr-ng/mL. For a 600 mg tablet the AUC_0-t may be selected from between 1,600 hr-ng/mL and 5,625 hr-ng/mL, 1,850 hr-ng/mL and Agent's File Reference: 62808.000021

5,250 hr-ng/mL, 2,000 hr-ng/mL and 4,750 hr-ng/mL, 2,125 hr-ng/mL and 4,500 hr-ng/mL, and 2,250 hr-ng/mL and 4,250 hr-ng/mL.

[0160] Alternatively, the low end of the AUCo-t for pseudoephedrine is preferably greater than 2,000 hr-ng/mL, more preferably 2,200 hr-ng/mL, more preferably 2,500 hr-ng/mL, and most preferably 2,800 hr-ng/mL depending on the formulation. The high end of the AUCo-_t for pseudoephedrine is preferably less than 6,000 hr-ng/mL, more preferably 5,750 hr-ng/mL, more preferably 5,500 hr-ng/mL, more preferably 5,250 hr-ng/mL, and most preferably 5,000 hr-ng/mL depending on the formulation. For a 120 mg tablet the AUC_0-t may be selected from between 2,000 hr-ng/mL and 6,000 hr-ng/mL, 2,200 hr-ng/mL and 5,750 hr-ng/mL, 2,500 hr-ng/mL and 5,500 hr-ng/mL, 2,700 hr-ng/mL and 5,250 hr- ng/mL, and 2,800 hr-ng/mL and 5,000 hr-ng/mL. For a 60 mg tablet the AUCo-_t may be selected from between 1,000 hr-ng/mL and 3,000 hr-ng/mL, 1,100 hr- ng/mL and 2,875 hr-ng/mL, 1,250 hr-ng/mL and 2,750 hr-ng/mL, 1,350 hr- ng/mL and 2,625 hr-ng/mL, and 1,400 hr-ng/mL and 2,500 hr-ng/mL.

[0161] Alternatively, the low end of the AUCo_-t for dextromethorphan is preferably greater than 59,000 hr-ng/mL, more preferably 119,000 hr-ng/mL, more preferably 143,000 hr-ng/mL, more preferably 162,000 hr-ng/mL, more preferably 166,000 hr-ng/mL, more preferably 182,000 hr-ng/mL, more preferably 190,000 hr-ng/mL, more preferably 202,000 hr-ng/mL, and most preferably 214,000 hr-ng/mL depending on the formulation. The high end of the AUCo-_t for dextromethorphan is preferably less than 475,000 hr-ng/mL, more preferably 360,000 hr-ng/mL, more preferably 337,500 hr-ng/mL, more preferably 333,000 hr-ng/mL, more preferably 309,000 hr-ng/mL, more preferably 300,000 hr-ng/mL, more preferably 286,000 hr-ng/mL, more preferably 270,000 hr-ng/mL, and most preferably 262,000 hr-ng/mL depending on the formulation. For a 60 mg tablet the AUC₀._t may be selected from between 216,000 hr-ng/mL and 337,500 hr-ng/mL, 243,000 hr-ng/mL and 300,000 hr- ng/mL, 243,000 hr-ng/mL and 270,000 hr-ng/mL, and 270,000 hr-ng/mL and 300,000 hr-ng/mL. For a 30 mg tablet the AUCo-t may be selected from between 162,000 hr-ng/mL and 250,000 hr-ng/mL, 182,000 hr-ng/mL and 230,000 hr- Agent's File Reference: 62808.000021

ng/mL, 182,000 hr-ng/mL and 202,000 hr-ng/mL, and 202,000 hr-ng/mL and 230,000 hr-ng/mL. In another embodiment the low end of the AUCo_-t for dextromethorphan is preferably greater than 15,000 hr-ng/mL, more preferably 18,000 hr-ng/mL, more preferably 21,000 hr-ng/mL, more preferably 24,000 hr- ng/mL, and most preferably 27,000 hr-ng/mL depending on the formulation. The high end of the AUCo-_t for dextromethorphan is preferably less than 47,300 hr- ng/mL, more preferably 45,000 hr-ng/mL, more preferably 42,000 hr-ng/mL, more preferably 39,000 hr-ng/mL, more preferably 36,000 hr-ng/mL, and most preferably 33,000 hr-ng/mL depending on the formulation.

[0162] Formulations of the invention provide a AUC_SS for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the AUC_SS for guaifenesin is preferably greater than 5000 hr- ng/mL, more preferably 5600 hr-ng/mL, more preferably 6000 hr-ng/mL, and most preferably 6500 hr-ng/mL depending on the formulation. The high end of the AUC_SS for guaifenesin is preferably less than 9000 hr-ng/mL, more preferably 8750 hr-ng/mL, more preferably 8250 hr-ng/mL, and most preferably 8000 hr-ng/mL depending on the formulation. The AUC_SS for a 1200 mg tablet may be selected from between 5000 hr-ng/mL and 9000 hr-ng/mL, 5600 hr- ng/mL and 8750 hr-ng/mL, 6000 hr-ng/mL and 8000 hr-ng/mL, and 6500 hr- ng/mL and 8250 hr-ng/mL. The AUC_SS for a 600 mg tablet may be selected from between 2,500 hr-ng/mL and 4,500 hr-ng/mL, 2,800 hr-ng/mL and 4,375 hr- ng/mL, 3,000 hr-ng/mL and 4,000 hr-ng/mL, and 3,250 hr-ng/mL and 4,125 hr- ng/mL.

[0163] Alternatively, the low end of the AUC_SS for pseudoephedrine is preferably greater than 2,100 hr-ng/mL, more preferably 2,400 hr-ng/mL, more preferably 2,650 hr-ng/mL, and most preferably 2,800 hr-ng/mL depending on the formulation. The high end of the AUC_SS for pseudoephedrine is preferably less Agent's File Reference: 62808.000021

than 5,500 hr-ng/mL, more preferably 5,000 hr-ng/mL, more preferably 4,500 hr-ng/mL, and most preferably 4,000 hr-ng/mL depending on the formulation. The AUC_ss for a 120 mg tablet may be selected from between 2,100 hr-ng/mL and 5,500 hr-ng/mL, 2,400 hr-ng/mL and 5,000 hr-ng/mL, 2,650 hr-ng/mL and 4,500 hr-ng/mL, and 2,800 hr-ng/mL 4,000 hr-ng/mL. The AUC_SS for a 60 mg tablet may be selected from between 1,050 hr-ng/mL and 2,250 hr-ng/mL, 1,200 hr-ng/mL and 2,500 hr-ng/mL, 1,325 hr-ng/mL and 2,250 hr-ng/mL, and 1,400 hr-ng/mL 2,000 hr-ng/mL. 4] Alternatively, the low end of the AUC_SS for dextromethorphan is preferably greater than 87,750 hr-ng/mL, more preferably 105,000 hr-ng/mL, more preferably 120,000 hr-ng/mL, more preferably 132,000 hr-ng/mL, more preferably 140,000 hr-ng/mL, and most preferably 158,000 hr-ng/mL depending on the formulation. The high end of the AUC_SS for dextromethorphan is preferably less than 263,000 hr-ng/mL, more preferably 245,000 hr-ng/mL, more preferably 228,000 hr-ng/mL, more preferably 220,000 hr-ng/mL, more preferably 210,000 hr-ng/mL, more preferably 197,000 hr-ng/mL, and most preferably 193,000 hr-ng/mL depending on the formulation. The AUC_SS for a 60 mg tablet may be selected from between 140,000 hr-ng/mL and 220,000 hr- ng/mL, 157,500 hr-ng/mL and 197,000 hr-ng/mL, 157,500 hr-ng/mL and 175,000 hr-ng/mL, and 175,000 hr-ng/mL and 197,000 hr-ng/mL. The AUC_SS for a 30 mg tablet may be selected from between 105,000 hr-ng/mL and 165,000 hr- ng/mL, 120,000 hr-ng/mL and 149,000 hr-ng/mL, 120,000 hr-ng/mL and 132,000 hr-ng/mL, and 132,000 hr-ng/mL and 149,000 hr-ng/mL. In another embodiment the low end of the AUC_SS for dextromethorphan is preferably greater than 19,000 hr-ng/mL, more preferably 22,800 hr-ng/mL, more preferably 26,600 hr-ng/mL, more preferably 30,500 hr-ng/mL, and most preferably 34,000 hr-ng/mL depending on the formulation. The high end of the AUC_SS for dextromethorphan is preferably less than 57,000 hr-ng/mL, more preferably 53,000 hr-ng/mL, more preferably 49,500 hr-ng/mL, more preferably 45,600 hr-ng/mL, and most preferably 41,800 hr-ng/mL depending on the formulation. Agent's File Reference: 62808.000021

[0165] Formulations of the invention provide a T^ for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the Tm for guaifenesin is preferably greater than 0.7 hours, more preferably 0.9 hours, more preferably 1.1 hours, more preferably 1.3 hours, and most preferably 1.4 hours depending on the formulation. The high end of the T_{1 2} for guaifenesin is preferably less than 7.25 hours, more preferably 6.0 hours, more preferably 5.0 hours, and most preferably 3.5 hours depending on the formulation. The T for a 1200 mg tablet may be selected from between 0.7 hours and 7.25 hours, 0.9 hours and 6.0 hours, 1.1 hours and 5.0 hours, 1.3 hours and 3.5 hours, and 1.4 hours and 3.5 hours. The Ty₂ for a 600 mg tablet may be selected from between 0.35 hours and 3.63 hours, 0.45 hours and 3.0 hours, .55 hours and 2.5 hours, .65 hours and 1.75 hours, and .70 hours and 1.75 hours.

[0166] Alternatively, the low end of the T ₂ for pseudoephedrine is preferably greater than 3.2 hours, more preferably 3.6 hours, more preferably 4.0 hours, more preferably 4.2 hours, and most preferably 4.5 hours depending on the formulation. The high end of the Ty for pseudoephedrine is preferably less than 8.0 hours, more preferably 7.5 hours, more preferably 7.0 hours, and most preferably 6.25 hours depending on the formulation. The T ₂ for a 120 mg tablet may be selected from between 3.2 hours and 8.0 hours, 3.6 hours and 7.5 hours, 4.0 hours and 7.0 hours, 4.2 hours and 6.25 hours, and 4.5 hours and 6.25 hours. The T ₂ for a 60 mg tablet may be selected from between 1.60 hours and 4.0 hours, 1.80 hours and 3.75 hours, 2.0 hours and 3.5 hours, 2.1 hours and 3.13 hours, and 2.25 hours and 3.13 hours.

[0167] Alternatively, the low end of the Tm for dextromethorphan is preferably greater than 4.6 hours, more preferably 5.6 hours, more preferably 6.5 hours, more preferably 7.0 hours, more preferably 7.4 hours, more preferably 7.9 hours, more preferably 8.4 hours, and most preferably 8.8 hours depending on the Agent's File Reference: 62808.000021

formulation. The high end of the T_1/2 for dextromethorphan is preferably less than 15.75 hours, 14.7 hours, more preferably 13.0 hours, more preferably 13.0 hours, more preferably 12.1 hours, more preferably 11.75 hours, more preferably 11.2 hours, and most preferably 10.2 hours depending on the formulation. The T_1/2 for a 60 mg tablet may be selected from between 9.4 hours and 14.7 hours, 10.6 hours and 13.2 hours, 10.6 hours and 11.75 hours, and 11.75 hours and 13.2 hours. The T ₂ for a 60 mg tablet may be selected from between 7.0 hours and 11.0 hours, 7.9 hours and 9.9 hours, 7.9 hours and 8.8 hours, and 8.8 hours and 9.9 hours.

[0168] Examples of other sustained release/immediate release formulations with and without additional drugs are discussed further in the examples which follow. EXAMPLES

[0169] The invention is further defined by reference to the following examples describing in detail the compositions and methods of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.

[0170] For the in vivo study portions, the following general procedures were used for sample analysis unless otherwise indicated. Blood samples (5-10 mLs with sodium heparin as anticoagulant) were taken prior to dosing and at specific intervals after dosing. All blood samples were chilled and centrifuged within 30 minutes of being drawn. The plasma was separated, transferred to a polypropylene tube, frozen at -20°C or below and stored frozen until being shipped for drag analysis. The plasma samples were then analyzed by a fully validated HPLC method. This resulting plasma concentration v. time data was subjected to pharmacokinetic analysis using non-compartmental analysis with Winnonlin 1.5.

[0171] When necessary, volunteers were then given at least a seven day washout period (where no guaifenesin was administered to them under the study) prior to being crossed-over to the next treatment group. Generally, the subjects weighed Agent's File Reference: 62808.000021

within 15% of their Ideal Body Weight as defined by the 1983 Metropolitan Life chart.

Example 1 [0172] A batch of sustained release guaifenesin tablets, LotNo. 7LB-31FC, with the following composition was prepared:

[0173] Another batch of sustained release guaifenesin tablets, Lot No. 7LB-32FC, with the following composition was prepared:

[0174] Six tablets from Lot 7LB-31FC and six tablets from Lot 7LB-32FC were tested for in vitro guaifenesin release using an Acid/Base dissolution (slightly modified USP 23/NF 18 <711> Drug Release using Apparatus 2). Six dissolution vessels of a USP calibrated Hanson dissolution bath, equipped with shafts and paddles, and were filled with 675 mL of 0. IN hydrochloric acid at 37.0°C. The bath and vessels were maintained at a temperature of 37.0 ± 0.5°C throughout the 12 hour dissolution test. The paddles were set to rotate at 50 RPM and slowly lowered into the vessels. One tablet of lot 7LB-31 was then dropped into each vessel.

[0175] At the one hour and two hour intervals of testing, 5 mL samples of dissolution solution were withdrawn from each vessel and filtered through a 10 micron polyethylene filter into glass HPLC vials. Immediately after the two hour samples were withdrawn, 225 mL of 0.2M sodium phosphate tribasic was Agent's File Reference: 62808.000021

added to each vessel to increase the solution pH to about 6.8. The dissolution was run for ten additional hours, 2.0 mL samples being withdrawn from each vessel at the four, eight, 10, and 12 hour intervals. The filtered samples were then run on an HPLC to determine percent guaifenesin released.

[0176] The same dissolution testing procedure was performed for lot 7LB-32 FC. The lots gave dissolution profiles shown below and depicted in Figure 4.

Lot 7LB-31

Lot 7LB-32FC

[0177] Both formulations demonstrated sustained release of guaifenesin over a 12 hour period. Lot 7LB-32FC demonstrated identical release properties to Lot

7LB-31FC in 0.1N HCl. In buffered solution, however, Lot 7LB-32FC, the lot comprising a 2:1 ratio of Methocel E10M to Carbopol 974P, demonstrated a statistically slower release than Lot 7LB-31FC, comprising Methocel E10M and no Carbopol 974P. A slower release rate in vitro translates to a slower, more controlled release with longer drug action in vivo - a favorable characteristic for pharmaceutical products containing a high concentration of an active ingredient with a short half-life (e.g. guaifenesin). Agent's File Reference: 62808.000021

Example 2 [0178] A dissolution study was run to compare dissolution profiles of lots 7LB- 32FC and 7LB-31FC with currently available guaifenesin dosage forms. One immediate release tablet, ORGANIDIN NR, and two sustained release tablets, HUMIBID L.A. and DURATUSS, were subjected to the same dissolution study as described for lots 7LB-31FC and 7LB-32FC in Example 1 above. The following is a summary of the results which are also depicted in Figure 5.

[0179] The immediate release Organidin released 100% of guaifenesin content within the first hour of dissolution. The two commercial sustained release dosage forms demonstrated a slower release of guaifenesin. However, both the Humibid LA and Duratuss released guaifenesin more rapidly than either Lot 7LB-31FC or 7LB-32FC, particularly after the eight hour interval. Both Humibid LA and Duratuss would, therefore, exhibit a faster rate of release and thus a shorter lived therapeutic effect in vivo. Example 3

[0180] The in vivo behavior of sustained release tablets of Lot 7LB-31FC and Lot 7LB-32FC from Example 1 were compared to the in vivo behavior of an immediate release formulation (Organidin NR). The open-label study involved 9 healthy volunteers averaging 38 ± 11.01 years of age with a range of 23 years to 55 years of age. The subjects weighed 175.56 ± 24.22 lbs. with a range of 143 to 210 lbs. One subject was female and the remainder was male. Each subject received either one 1200 mg dose of 7LB-31FC, 7LB-32FC or a commercial 400 mg immediate release tablet (every four hours for 3 doses). Agent's File Reference: 62808.000021

[0181] The results of the pharmacokinetic parameters analysis are described below and depicted in Figure 6.

[0182] Subjects given the 1200 mg formulation 7LB-32FC reached maximum plasma guaifenesin concentrations of 1016 ng/mL in 1.25 hours and had an AUQ_nf of 7663 hr-ng/mL. The subjects given formulation 7LB-31FC reached maximum plasma guaifenesin concentrations of 821 ng/mL in 1.67 hours and had an AUQ„_f of 5453 hr-ng/mL. The subjects given the immediate release formulation, Organidin NR, reached maximum plasma guaifenesin concentrations of 2263 ng/mL in 1.75 hours (2 subjects peaked at 0.5 hours after the first dose and the third peaked at 0.25 hours after the second dose at 4 hours) and had an AUQ_nf of 7752 hr-ng/mL. The two controlled release formulations demonstrated sustained release in that their half-lives were longer, 5.77 hours for the 7LB-32FC and 3.59 hours for the 7LB-31 FC compared to 0.8 hours for the immediate release formulation, Organidin NR.

[0183] Both formulations 7LB-32FC (with both Methocel E10M and Carbopol 974P) and 7LB-31FC (with Methocel E10M only) control the release of guaifenesin from the tablet compared to the immediate release Organidin NR. Formulation 7LB-32FC, the formulation containing a 6:1 ratio of Methocel Agent's File Reference: 62808.000021

EIOM to Carbopol 974P, had the longest half life at 5.77 hours with the largest AUCi_nf between the two sustained release formulation. However, both sustained release formulations have a C_max less than half of the C_maχ of the immediate release Organidin NR. Example 4

[0184] Three different sustained release tablet lots of guaifenesin alone were prepared: i) Formulation I - 1200 mg SR; ii) Formulation II - 400 mg IR and 800 mg SR; and iii) Formulation HI - 600 mg IR and 600 mg SR.

Non-layered tablet (sustained release)

Formulation I

Bi-layered tablets (sustained release and immediate release)

Immediate release layer

Formulation II Formulation III

Sustained release layer

Formulation II Formulation III

Agent's File Reference: 62808.000021

[0185] The in vivo behavior of each of the three sustained release tablets and a commercial immediate release formulation (Organidin NR) were compared. The open-label study involved 15 healthy volunteers averaging 31.67 ± 11.89 years of age with a range of 20 years to 51 years of age. The subjects weighed 162.00 + 25.05 lbs. with a range of 123 to 212 lbs. All 15 subjects were administered 400 mg of the immediate release formulation every 4 hours for a total of 12 hours in on one day. On another day, 5 subjects were administered Sustained Formulation I, another 5 subjects were administered Sustained Formulation II, and yet another 5 subjects were administered Sustained Formulation III.

[0186] The results of the pharmacokinetic parameters analysis are described below and depicted in Figure 7.

[0187] Sustained Formulations II and III exhibited a C_maχ more comparable to the immediate release formulation and an increased AUQ_nf from that of the non- layered Sustained Formulation I. The half-lives of both Sustained Formulation II and HI were reduced from the half-life of Sustained Formulation I. These bi- layer tablets, however, showed an improved serum concentration of guaifenesin and an increased overall concentration with time. Example 5

[0188] A dissolution study was run to compare dissolution profiles of Formulation I, Formulation II and Formulation HI prepared as defined in Example 4 above, and Formulation TV, a bi-layer tablet lot with 200 mg IR and 1000 mg SR prepared with the following composition: Agent's File Reference: 62808.000021

Immediate release layer

Formulation IV

Sustained release layer

Formulation IV

The following is a summary of the results which are also depicted in Figure 8.

[0189] Formulation I, the non bi-layered tablet, demonstrated the slowest release of guaifenesin. Formulation II and Formulation III had the fastest rates of release and would, therefore, exhibit a faster rate of release and thus a shorter lived therapeutic effect in vivo. Formulation IN has a rate of release which was faster than Formulation I, comprising no immediate release blend, but slower than Formulation II and Formulation HI, both comprising more immediate release blend than Formulation IN. Agent's File Reference: 62808.000021

Example 6

[0190] The in vivo behavior of Formulation IN bi-layered tablets, prepared as described above in Example 5, was compared to an immediate release formulation (Organidin ΝR). The open-label, multiple dose, randomized, 2-way crossover study involved 26 healthy volunteers averaging 31.31 ± 9.81 years of age with a range of 19 years to 50 years of age. The subjects weighed 166.77 ± 29.83 lbs. The subjects were placed into one of two treatment groups. Group 1 received Formulation IN tablet with 240 mL of water after an overnight fast every 12 hours for 5 days and a single dose on day 6. Group 2 received 400 mg of Organidin ΝR (2 x 200 mg tablets) with 240 mL of water every 4 hours for 5 days and one 400 mg dose every four hours for a total of 3 doses on day 6.

[0191] Blood samples (5 mL with sodium heparin as anticoagulant) were taken prior to dosing on days 1, 4, 5, and 6. On Day 1, additional blood samples (5 mL with sodium heparin as anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10. 11, and 12 hours after the initial dose. On Day 6, additional blood samples (5 mL with sodium heparin as anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 1, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, and 24 hours after the initial dose.

[0192] The results of the pharmacokinetic parameters analysis are below.

Averaged Testing - 11 Twelve-Hour intervals

The results of the testing are depicted in Figure 9. Steady State Testing

[0193] The results of the testing are depicted in Figure 10. Agent's File Reference: 62808.000021

[0194] The 200/1000 mg bi-layered tablet exhibited a C_max and a AUQ_nf equivalent to that of the immediate release blend, a short T_max and an extended half-life. Thus, a bi-layered tablet with 200 mg guaifenesin in the immediate release formulation and 1000 mg of guaifenesin in the sustained release formulation results in a tablet which delivers a high seram concentration in a short period of time, yet maintains an effective concentration of guaifenesin in the blood stream for a full twelve hours. Example 7

[0195] A study was performed to examine the relative bioavailability of two different dosage strengths of modified release guaifenesin formulations of the invention as well as the effect of food on the relative bioavailability of a guaifenesin formulation of the invention in normal, healthy male and/or female volunteers. Two batches of guaifenesin bi-layer tablets, one 600 mg and one 1200 mg, were prepared.

Immediate release layer

600 mg Tablet 1200 mg Tablet

Sustained release layer

600 mg Tablet 1200 mg Tablet

Agent's File Reference: 62808.000021

[0196] The 600 mg and 1200 mg tablets were similarly prepared, the with the exception of the number of tablets produced from the amount of materials used.

[0197] The in vivo behaviors of a 600 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing), the 1200 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing), and the 1200 mg tablet administered to volunteers after a high fat meal (consumed within 30 minutes of dosing) were compared. The open-label study involved 27 healthy volunteers between the ages of 18 and 55. The 27 volunteers were divided into 3 treatment groups, 9 receiving the 600 mg tablet, 9 receiving the 1200 mg tablet while fasting, and 9 receiving a 1200 mg tablet after consuming a high fat meal for Period 1 of the trial. After completion of Period 1, the volunteers were crossed-over for Period 2 (e.g. so that the 9 volunteers who had been receiving the 600 mg tablet in Period 1 received the 1200 mg tablet while fasting in Period 2). After completion of Period 2, the volunteers were crossed-over again into their 3rd and final treatment group (i.e. the 9 volunteers who received the 1200 mg tablet while fasting in Period 2 and the 600 mg tablet while fasting in Period 1 received the 1200 mg tablet after consumption of a high fat meal in Period 3). Each volunteer was administered one dose of the appropriate tablet and then monitored over a 16 hour period.

[0198] Blood samples were taken about one hour prior to dosing and at specific intervals up to 16 hours after dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours). The results of the pharmacokinetic parameters analysis are described below and in Figure 11.

[0199] The 600 mg tablet demonstrated a seram profile approximately directly proportional to the seram profile of the 1200 mg tablet. The C_max of the 600 mg tablet was about 55% that of the 1200 mg tablet. The AUC_0-12 of the 600 mg Agent's File Reference: 62808.000021

tablet was about 48% that of the 1200 mg tablet and the AUQ_nf of the 600 mg tablet was about 46% that of the 1200 mg. improved serum concentration of guaifenesin and an increased overall concentration with time, their half-life was compromised.

[0200] The 1200 mg tablet demonstrated that the bi-layer tablets of the invention greatly reduce the food effect in bioavailability and seram concentration of guaifenesin. The C_max of the 1200 mg tablet administered after a high fat meal (fed tablet) was about 102% of the C_max of the 1200 mg tablet administered after fasting (fasted tablet). The AUCo^a of the 1200 mg fed tablet was about 99% that of the fasted tablet and the AUQ_nf of the 1200 mg fed tablet was about 94% that of the fasted tablet. Example 8

[0201] In an example of a combination drug formulation, two batches of guaifenesin/dextromethorphan HBr bi-layer tablets were prepared: i) 600 mg/ 30 mg dextromethorphan and ii) 1200 mg/ 60 mg. In the 30 mg dextromethorphan tablet 7.5 mg was within the immediate release layer and 22.5 mg within the sustained release layer. The 60 mg dextromethorphan tablet comprised double the dextromethorphan respectively.

[0202] Sustained release layer

600 mg/ 30 mg 1200 mg/ 60 mg

Agent's File Reference: 62808.000021

Immediate release layer

[0203] The following is a summary of 1200 mg guaifenesin/ 60 mg dextromethoφhan HBr Dissolution Rate for three different batches also depicted in Figure 12.

[0204] The in vivo behavior of the 1200 mg guaifenesin and 60 mg tablet was studied by measuring the plasma concentration of guaifenesin, dextromethorphan HBr, and the metabolite dextrorphan. Figures 13-15 illustrate the plasma concentration for each drag or metabolite in two formulations, Formulation B and Formulation C, during a 24 hour period. Immediately after administration the plasma concentration of guaifenesin peaks in about an hour, followed by a gradual plasma concentration decrease over 24 hours. Immediately after administration, guaifenesin plasma concentration never decreased to less than 200 ng/mL over 12 hours. Thereafter, guaifenesin plasma concentration gradually decreased over the next 12 hours. Plasma concentration of dextromethorphan HBr peaks at about 6 hours at about 12 ng/mL and the concentration is maintained for the following 19 hours. Agent's File Reference: 62808.000021

[0205] Formulations B and C of Figure 13, exhibited guaifenesin release profiles similar to the reference formulation. The reference formulation for Figure 13 was Formulation TV of Example 5. Formulation B comprised 77% guaifenesin by weight, 3.8% by weight dextromethorphan, 9.1% by weight microcrystalline cellulose, 1.9% by weight Methocel E10M, and 0.9% Carbopol® 974P. Formulation C comprised 76.5% by weight guaifenesin, 3.8% by weight dextromethorphan, 9.7% by weight microcrystalline cellulose, 1.9% by weight Methocel E10M, and 0.9% by weight Carbopol® 974P. Formulations B and C exhibited similar behavior and had a guaifenesin release profile similar to the reference formulation. Accordingly, the combination formulations of the invention did not interfere with the release of guaifenesin. In particular, after 12 hours Formulation C released a greater dose of guaifenesin than the reference formulation.

[0206] Formulations B and C of Figure 13 were compared against a reference consisting of an extended release formulation of dextromethorphan commercially available under the name Delsym sold by Celltech. The comparison was carried out to determine the behavior of guaifenesin- dextromethorphan formulations of the invention as compared to separately administered combination formulations of dextromethorphan. Formulations B and C had longer dextromethorphan release profiles than the reference, as shown in Figure 14. Additionally, the combined formulations of the inventions had no detrimental effect upon the release profile of dextromethorphan.

[0207] Another method to monitor dextromethorphan plasma concentrations is to measure the plasma concentration of the metabolite dextrorphan. The plasma concentration of dextrorphan metabolite of the reference formulation and Formulations B and C of Figure 14 were plotted in Figure 15. Generally, the formulations exhibited similar dextrorphan concentrations, with Formula C exhibiting the highest dextrorphan concentration after 12 hours. Figure 15 demonstrates that the formulations of the invention containing guaifenesin do not inhibit the release of dextromethorphan, as determined by measuring the presence of the metabolite dextrorphan. Agent's File Reference: 62808.000021

Example 9

[0208] A study was performed to examine the relative bioavailability of a sustained release guaifenesin with dextromethorphan formulation of the invention with normal, healthy male and/or female volunteers. A batch of guaifenesin and dextromethorphan bi-layer tablet, 1200 mg, was prepared according to the composition described above for Example 8.

[0209] The in vivo behaviors of the 1200 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing) was determined. The open-label study involved 29 healthy volunteers between the ages of 18 and 55. The 29 volunteers were divided into two treatment groups half receiving the 1200 mg tablet while fasting for Period 1 of the trial. Each volunteer was administered one dose of the appropriate tablet and then monitored over a 16 hour period.

[0210] Blood samples (7 mL with sodium heparin as anticoagulant) were taken about one hour prior to dosing and at specific intervals up to 16 hours after dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours). The results of the pharmacokinetic parameters analysis for guaifenesin include a T_maχ of 1.48 hr, Cm_ax (ng/mL) of 2196, AUC₀-ι₂ (hr-ng/mL) of 8702, T_1/2of 1.32 hrs., and an AUQ_nf (hr-ng/mL) of 8732.5. The results of the pharmacokinetic parameters analysis for dextromethorphan include a T_maχ of 5.0 hrs, C_maχ (pg/mL) of 5157, AUC₀-ι₂ (hr-pg/rxiL) of 74209, T_1/2 of 7.93 hrs., and an AUQ_nf (hr-pg/mL) of 75016. Example 10

[0211] In another example of a combination formulation, two batches of guaifenesin-pseudoephedrine HCl bi-layer tablets, one 600 mg and one 1200 mg, were prepared in the following amounts. Agent's File Reference: 62808.000021

Sustained release layer

600 mg/ 60 g 1200 mg/ 120 mg

Immediate release layer

600 mg/ 60 mg 1200 mg/ 120 mg

[0212] The following is a summary of 1200 mg guaifenesin/ 120 mg pseudoephedrine dissolution rates also depicted in Figure 16.

[0213] The in vivo behavior of the 1200 mg guaifenesin and 120 mg pseudoephedrine tablet was studied by measuring the plasma concentration of guaifenesin, and pseudoephedrine HCl. The three batches of the 1200 mg Agent's File Reference: 62808.000021

guaifenesin/ 120 mg pseudoephedrine HCl formulation were dissolved to determine the amount of pseudoephedrine HCl released over time. Generally, the formulations had 1200 mg of guaifenesin and 120 mg pseudoephedrine HCl and were studied over a 12 hour period. The released amount of pseudoephedrine HCl was determined as a weight percent of dissolved pseudoephedrine HCl in contrast to the total weight of pseudoephedrine HCl prior to dissolution. After 1 hour about 43% to 45% of the pseudoephedrine HCl had dissolved. After 2 hours the about 58% to 60% dissolved, after 6 hours 82% to 89% had dissolved, and after 12 hours about 96% to 97% by weight of the pseudoephedrine HCl had dissolved. (See Figure 16).

[0214] Three formulations of guaifenesin, two containing an additional drug, pseudoephedrine, were compared to determine whether an additional drug affects the release profile of guaifenesin. Figures 17-18 illustrate the plasma concentration for each drug (Formulation B and Formulation C) during a 24 hour period. Immediately after administration the plasma concentration of guaifenesin peaks in about an hour, followed by a gradual plasma concentration decrease over 24 hours. Immediately after administration, guaifenesin plasma concentration never decreased below 200 ng/mL over 12 hours. Thereafter, guaifenesin plasma concentration gradually decreased over the next 12 hours. Plasma concentration of pseudoephedrine HCl peaked at about 6 hours and gradually decreased over the next 18 hours. The plasma concentration of pseudoephedrine HCl never decreased to less than 50 ng/mL after 30 minutes of administration.

[0215] In Figure 17, the reference formulation included formulation IN of Example 5 and a separate Sudafed® 12 hour formulation available from Pfizer Inc. 201 Tabor Road, Morris Plains, New Jersey, 07950. The reference formulation was compared to Formulation B and Formulation C of the invention. Formulation B comprised a sustained release formulation having 86% by weight Guaifenesin DC, 9.8% by weight pseudoephedrine HCl, 2.4% by weight hydroxypropyl methylcellulose, and 1.2% by weight Carbopol® 974P, and an immediate release formulation having 52% by weight Guaifenesin DC and 39% by weight Agent's File Reference: 62808.000021

microcrystalline cellulose by weight. Formulation C comprised 77% by weight Guaifenesin DC, 7.7% by weight pseudoephedrine, 9% by weight microcrystalline cellulose, 1.8% by weight Methocel E10M, and 0.9% by weight Carbopol® 974P. Formulations B and C exhibited similar behavior to separately administered formulations, thus demonstrating that formulations of the invention did not interfere with the profile release of pseudoephedrine.

[0216] The plasma concentration for pseudoephedrine HCl was studied to determine whether the formulations of the invention interfered with the release profile of pseudoephedrine. The pseudoephedrine plasma concentrations for the formulations of Figure 17 were plotted over a 24 hour period. As illustrated in Figure 18, Formulations B and C of Figure 17 exhibited higher pseudoephedrine concentrations than the reference formulation. Thus, the combined formulations of the invention release pseudoephedrine in comparable or better release profiles than formulations containing pseudoephedrine alone. Example 11

[0217] A study was performed to examine the relative bioavailability of sustained release guaifenesin with pseudoephedrine formulations of the invention in normal, volunteers. A batch of guaifenesin and pseudoephedrine bi-layer tablets, 1200 mg, was prepared according to the composition described above for Example 10.

[0218] The in vivo behaviors of a 1200 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing) were compared. The open-label study involved 29 healthy volunteers between the ages of 18 and 55. The 29 volunteers were divided into two treatment groups, half receiving the 1200 mg tablet while fasting for Period 1 of the trial. Each volunteer was administered one dose of the appropriate tablet and then monitored over a 16 hour period.

[0219] Blood samples (7 mL with sodium heparin as anticoagulant) were taken about one hour prior to dosing and at specific intervals up to 16 hours after dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours). The results of the pharmacokinetic parameters analysis for guaifenesin include a T_maχ Agent's File Reference: 62808.000021

of 1.48 hr, C_max (ng/mL) of 2196, AUC₀.₁₂ (hr-ng/mL) of 8702, T_{1 2} of 1.32 hrs., and an AUQ_nf (hr-ng/mL) of 8732.5. The results of the pharmacokinetic parameters analysis for pseudoephedrine include a T_maχ of 6 hrs, C_maχ (ng/mL) of 300, AUC_0-12 (hr-ng/mL) of 4201, Tι ₂ of 5.98 hrs., and an AUQ_nf (hr-ng/mL) of 4709.

Example 12

[0220] Guaifenesin and pseudoephedrine sustained release formulations were compared to commercial controlled release guaifenesin and pseudoephedrine products in healthy volunteers in an open label, single dose, randomized, 3-way crossover study in 15 subjects.

[0221] The subjects were randomized and placed into one of three treatment groups. Group A was given Formulation A, one 1200 mg controlled release guaifenesin product (Mucinex) plus a 120 mg controlled release pseudoephedrine hydrochloride product (Sudafed- 12 Hour) with 240 mL of water after an overnight fast. Group B received Formulation B (lot PB01-K61), an experimental controlled release tablet containing 1200 mg guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 mL of water after an overnight fast. Group C received Formulation C (lotCBOO-OlA), another experimental controlled release tablet containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water after an overnight fast. There was at least a 7-day washout between doses.

[0222] The volunteers averaged 26.4 ± 10.57 years of age (Mean ± Standard Deviation) with a range of 18 years to 50 years of age. They were 66.93 ± 4.37 inches tall with a range of 60 to 74 inches. They weighed 160.87 ± 26.22 pounds with a range of 118 to 222 pounds. Seven were male (47%) and eight female (53%). Ten (67%) of the subjects had a large frame size, three (20%) had a medium frame and two (13%) had a small frame. Thirteen volunteers (87%) were Caucasian and two (13%) were Multiracial. Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose. Agent's File Reference: 62808.000021

[0223] Subjects given 1200 mg of guaifenesin as guaifenesin ER (reference) reached a C_maχ of 1847 ng/mL in 0.78 hours and had an AUQ„_f of 7302 hr- ng/mL. Subjects given 1200 mg guaifenesin as Formulation B reached a C_max of 1784 ng/mL (103% of that of the reference) in 0.82 hour (113% of that of the reference) and had an AUQ_nf of 7602 hr-ng/mL (109% of that of the reference). Subjects given 1200 mg guaifenesin as Formulation C reached a C_maχ of 1154 ng/mL (65% of that of the reference) in 1.22 hours (179% of that of the reference) and had an AUQ_nf of 7128 hr-ng/mL (100% of that of the reference).

[0224] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed-12 Hour (reference) reached a C_max of 300 ng/mL (mean ± standard deviation) in 6 hours and had an AUQ_nf of 4710 hr-ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as Formulation B reached a C_maχ of 285 ng/mL (99% of that of the reference) in 6 hours (101% of that of the reference) and had an AUQ_nf of 4449 hr-ng/mL (100% of that of the reference). Subjects given 120 mg pseudoephedrine hydrochloride as Formulation C reached a C_max of 256 ng/mL (86% of that of the reference) in 8 hours (151% of that of the reference) and had an AUQnf of 4444 hr-ng/mL (97% of that of the reference).

[0225] The plasma concentrations of guaifenesin are depicted in Figure 19. The resulting pharmacokinetic data is shown in Tables 1 through 4. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex were 1847 ± 686.6 ng/mL and occurred in 0.78 ± 0.28 hours. The resulting area under the plasma concentration vs. time curve (AUQ_nf was 7302 ± 2866.4 hr- ng/mL. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Formulation B were 1784 ± 549.9 ng/mL (102.93% ± 36.57% of that of the reference formulation) and occurred in 0.82 ± 0.27 hours (112.78% ± 43.29% that of the reference formulation). The resulting AUQ_n was 7602 ± 2492.8 hr-ng/mL (108.67% ± 23.93% of that of the reference formulation). The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Formulation C were 1154 ± 523.3 ng/mL (64.56% ± 28.03% of that of the reference formulation) and occurred in 1.22 ± 0.45 hours (178.9% ±100.64% Agent's File Reference: 62808.000021

that of the reference formulation). The resulting AUQ_nf was 7128 ± 3166.0 hr ng/mL(99.81% ± 34.23% of that of the reference formulation).

Agent's File Reference: 62808.000021

[0226] The plasma concentrations of pseudoephedrine are depicted in Figure 20. The resulting pharmacokinetic data is shown in Tables 5 through 9. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed-12 Hour (reference) were 300.3 ± 91.44 ng/mL and occurred in 6 ± 1.69 hours. The resulting AUQ_n was 4710 ± 1394.5 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Formulation B were 285.3 ± 53.28 ng/mL (99.3 1% ± 20.39% of that of the reference formulation) and occurred in 5.80 ± 2.40 hours (101.11% ± Agent's File Reference: 62808.000021

41.77% of that of the reference formulation). The resulting AUQ_nf was 4449 ± 1079.6 hr-ng/mL (99.87% ± 26.40% of that of the reference formulation). The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Formulation C were 256.4 ± 80.7 ng/mL (86.37% ± 14.38% of that of the reference formulation) and occurred in 8.27 ± 2.71 hours (5 1.11% ± 73.25% of that of the reference formulation). The resulting AUQ_nf was 4444 ± 1212.1 hr-ng/mL (96.78% ± 17.90% of that of the reference formulation).

Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0227] The data indicates that both formulations produce optimum guaifenesin bioavailability (although Formulation B appears to more closely match the reference) and Formulation B produces optimal pseudoephedrine bioavailability. Example 13

[0228] The bioavailability of a sustained release combination formulation of 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride was used to examine the dose proportionality of Pseudoephedrine normal volunteers compared to reference guaifenesin and Pseudoephedrine Hydrochloride in an open label, single dose, randomized, 3-way crossover study with 36 subjects. The example also demonstrates the dose proportionality of pseudoephedrine.

[₀₂2₉] The subjects were randomized and placed into one of three treatment groups. Group I received Treatment A, a 1200 controlled release guaifenesin product (Mucinex) plus a 120 mg controlled release pseudoephedrine product (Sudafed® 12 Hour) with 240 mL of water after an overnight fast (Reference). Group 2 received Treatment B(PB01-M65A2), an experimental controlled release formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water after an overnight fast (test). Group 3 received Treatment C(PB01-A12A), an experimental controlled release Agent's File Reference: 62808.000021

formulation containing 600 mg guaifenesin and 60 mg pseudoephedrine with 240 mL of water after an overnight fast.

[₀23₀] The volunteers averaged 23.06 ± 7.05 years of age (Mean ± Standard Deviation) with a range of 18 years to 48 years of age. They were 70.58 ± 3.08 inches tall with a range of 64 to 75 inches. They weighed 167.42 ± 26.14 pounds with a range of 114 to 229 pounds. Twenty-four were male (67%) and twelve female (33%). Sixteen (44%) of the subjects had a large frame size, thirteen (36%) had a medium frame and seven (19%) had a small frame. Thirty-two volunteers (89%) were Caucasian, three (8%) were Black and one (3%) Multiracial. Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose (the total blood loss for guaifenesin and pseudoephedrine analysis will be 450 mL).

[0231] Subjects given 1200 mg of guaifenesin as Mucinex and 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour (Treatment A, Reference) reached a C_maχ of 1940 ng/mL in 0.77 hours and had an AUQ_nf of 8061 hr- ng/mL. Subjects given 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride as Treatment B (Test) reached a C_max of 1813 ng/mL (98% of that of the reference) in 1.04 hour (140% of that of the reference) and had an AUCo-∞ of 8124 hr ng/mL (101% of that of the reference). Subjects given 600 mg guaifenesin and 60 mg pseudoephedrine hydrochloride as Treatment C reached a C_max of 920 ng/mL (54% of that of the reference) in 0.99 hours (116% of that of the reference) and had an AUQ_nf of 3565 hr-ng/mL (46% of that of the reference).

[0232] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour and 1200 mg guaifenesin as Mucinex (Treatment A, Reference) reached a mean C_max of 250 ng/mL in 6 hours and had an AUQ_nf of 3847 hr-ng/mL. Subjects given 120 mg pseudoephedrine and 1200 mg guaifenesin as an experimental formulation (Treatment B, Test) reached a of 263 ng/mL (107% of that of the reference) in 5 hours (85% of that of the reference) and had an AUQ_nf of 3884 hr-ng/mL (103% of that of the reference). Subjects given 60 mg Agent's File Reference: 62808.000021

pseudoephedrine hydrochloride and 600 mg guaifenesin in an experimental formulation (Treatment C) reached a C_max of 141 ng/mL (54% of that of Formulation B) in 5 hours (100% of that of Formulation B) and had an AUQ_nf of 1968 hr-ng/mL (50% of that of Formulation B).

[0233] Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose. Bioequivalence was examined between the test (Treatment B - guaifenesin or pseudoephedrine hydrochloride experimental formulation) and the reference (Treatment A - guaifenesin or pseudoephedrine hydrochloride reference formulations) groups. The dose response relationship was also examined between the test (Treatment B- guaifenesin or pseudoephedrine hydrochloride experimental formulation) and the reference (Treatment C - guaifenesin or pseudoephedrine hydrochloride reference formulations) groups.

[0234] The plasma concentrations of guaifenesin is depicted in Figure 21. The resulting pharmacokinetic data is shown in Tables 10 through 14. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex and 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour were 1940 ± 889 ng/mL and occurred in 0.77 ± 0.22 hours. The resulting area under the plasma concentration vs. time curve (AUQ_nf was 8061 ± 3329 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Treatment B were 1813 ± 900 ng/mL (98.1% ± 35.8% of that of the reference formulation) and occurred in 1.04 ± 0.49 hours (140%+ 65.3% that of the reference formulation). The resulting AUQ_nf was 8124 ± 3677 hr-ng/mL (101% ± 19.3% of that of the reference formulation). The maximum plasma concentrations of guaifenesin following a 600 mg oral dose as Treatment C were 920 ± 481 ng/mL (54.3% ± 20.2% of that of the reference formulation) and occurred in 0.99 ± 0.46 hours (116% ± 78.7% that of the reference formulation). The resulting AUQ_nf was 3565 ± 1442 hr-ng/mL (45.6% ± 10.2% of that of the reference formulation). Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0235] The plasma concentrations of pseudoephedrine are depicted in Figure 22. The resulting pharmacokinetic data is shown in Tables 15 through 19. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour and 1200 mg guaifenesin as Mucinex (Treatment A, Reference) were 250 ± 53.4 ng/mL and occurred in 6.29 ± 1.76 hours. The resulting AUQ_nf was 3847 ± 910 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as an experimental formulation (Treatment B) were 263 ± 58.5 ng/mL (107% ± 18.9% Agent's File Reference: 62808.000021

of that of the reference formulation) and occurred in 5.11 ± 1.78 hours (85.2% ± 31.5% of that of the reference formulation). The resulting AUQ_nf was 3884 ± 911 hr-ng/mL (103% ± 20.2% of that of the reference formulation). The maximum plasma concentrations of pseudoephedrine following a 60 mg oral dose as an experimental formulation (Treatment C) were 141 ± 30.3 ng/mL (53.5% ± 6.52% of that of Formulation B) and occurred in 4.94 ± 1.60 hours (99.5% ± 25.9% of that of Formulation B). The resulting AUQ_nf was 1968 ± 477 hr-ng/mL (50.5% ± 8.77% of that of Formulation B).

Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0236] In conclusion, the experimental formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride is bioequivalent to the reference formulations given is separate doses. In addition the pharmacokinetics of guaifenesin and pseudoephedrine are linear over the range studied. Example 14

[0237] The effects of a high fat meal on the bioavailability of a combination formulation were tested. The bioavailability of a 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride formulation volunteers was compared to reference drug bioavailability in an open-label, single-dose, randomized, 2-way- crossover study using 36 subjects.

[0238] The subjects were randomized and placed into one of two treatment groups. Group 1 received a 1200-mg controlled-release guaifenesin product (Mucinex) and 120 mg pseudoephedrine hydrochloride (Sudafed® 12 Hour) with 240 mL of water, 30 minutes after the beginning of the consumption of a high-fat breakfast (Reference). Group 2 received an experimental formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water, 30 minutes after the beginning of the consumption of a high-fat breakfast (Test)(PB01-M65A3).

[0239] Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post Agent's File Reference: 62808.000021

dose (the total blood loss for guaifenesin and pseudoephedrine analysis was 300 mL).

[0240] Subjects given 1200 mg of guaifenesin as Mucinex (Reference) reached a C_max of 2207 ng/mL in 1.85 hours and had an AUQ_nf of 8067 hr-ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation (Treatment B) reached a of 1649 ng/mL (79% of that of the Reference) in 1.84 hour (118% of that of the Reference) and had an AUQ_nf of 7663 hr-ng/mL (93% of that of the Reference).

[0241] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour (Reference) reached a C_max of 268 ng/mL in 6.38 hours and had an AUQ_nf of 3636 hr-ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as an experimental formulation (Treatment B) reached a C_max of 274 ng/mL (103% of that of the Reference) in 4.80 hours (76.5% of that of the Reference) and had an AUQ_nf of 3528 hr-ng/mL (96.5% of that of the Reference).

[0242] Additionally, bioequivalence data was examined between the Test group (Treatment B - 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation) and the Reference group (Treatment A - the reference 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride formulations).

[0243] The plasma concentrations of guaifenesin are depicted in Figure 23. The resulting pharmacokinetic data are shown in Tables 20 through 22. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex were 2207 ± 952 ng/mL and occurred in 1.85 ± 1.06 hours. The resulting area under the plasma concentration vs. time curve (AUQ_nf was 8067 ± 2663 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a 1200-mg oral dose as an experimental formulation (Treatment B) was 1649 ± 690 ng/mL (79% ± 31.5% of the Reference formulation) and occurred in 1.84 ± 0.818 hours (118% ± 68.8% of the Reference formulation). The resulting AUQ_nf was 7663 ± 2864 hr-ng/mL (93% ± 17.6% of that of the Reference formulation). Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0244] The plasma concentrations- of pseudoephedrine are depicted in Figure 24. The resulting pharmacokinetic data are shown in Tables 23 through 25. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour (Reference) was 268 ± 69.7 ng/mL and occurred in 6.38 ± 1.26 hours. The resulting AUQ_nf was 3636 ± 940 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as an experimental formulation (Treatment B) was 274 ± 72.3 ng/mL (103% ± 10.3% of that of the Reference formulation) and occurred in 4.80 ± 1.28 hours (76.5% ± 23.1% of that of the Reference formulation). The resulting AUCinf was 3528 ± 962 hr-ng/mL (96.5% ± 11.7% of that of the Reference formulation).

Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0245] The rate of absorption of guaifenesin from the experimental formulation, as assessed by C_max is not bioequivalent to the test formulation in the presence of a high fat meal with a 95% confidence interval between 67.9% and 81.8%. The extent of absorption of guaifenesin from the experimental tablet, as assessed by AUCi_nf is equivalent to the test formulation in the presence of a high fat meal.

[0246] In conclusion, the rate of guaifenesin absorption from the experimental formulation is not bioequivalent to the Reference formulations; whereas the extent of guaifenesin absorption is bioequivalent to the Reference formulation in the presence of a high-fat meal. The rate and extent of pseudoephedrine absorption from the experimental formulation are bioequivalent to the Reference formulation in the presence of a high-fat meal. Example 15

[0247] A combination guaifenesin and Pseudoephedrine formulation was tested for steady state pharmacokinetics as compared to references in an open-label, multiple-dose, randomized, 2-way-crossover study using 36 subjects. The subjects were randomly placed into one of two treatment groups. Group 1 received a 1200 mg controlled-release guaifenesin product (Mucinex) plus a 120 mg controlled-release pseudoephedrine product (Sudafed® 12 Hour) with 240 mL of water after an overnight fast and again 12 hours later for 11 doses (Reference). Group 2 received an experimental controlled-release formulation Agent's File Reference: 62808.000021

comprising 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water after an overnight fast and again 12 hours later for 11 doses (Test)(PB01-M65).

[0248] Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose blood sample before the AM dose on Days 1, 4, 5 and 6. On Day 6 additional blood samples (5 mL, sodium heparin anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours after the last dose (total blood loss for guaifenesin determination was 380 mL).

[0249] The subjects given 1200 mg guaifenesin, as Mucinex every 12 hours for 11 doses, reached a maximum steady-state plasma guaifenesin concentration of 1960 ng/mL at 0.81 hours after the last dose (120.81 hours after the first dose). The mean AUC_SS was 7209 hr-ng/mL and the mean C_mj_n was 52 ng/mL.. Those subjects given 1200 mg guaifenesin, as an experimental formulation every 12 hours for 11 doses, reached a maximum steady-state plasma guaifenesin concentration of 1983 ng/mL (103% of the Reference formulation) at 0.96 hours after the last dose (120.96 hours after the first dose, 100% of that of the Reference formulation). The mean AUC_SS was 8183 hr-ng/mL (114% of that of the Reference formulation) and the mean C_mi_n was 117 ng/mL.

[0250] At steady state, the subjects given 120 mg pseudoephedrine hydrochloride, as Sudafed® 12 Hour, every 12 hours for 11 doses, reached a steady-state maximum plasma pseudoephedrine concentration of 361 ng/mL at 4.89 hours after the last dose (124.89 hours after the first dose). The mean AUC_SS was 3528 hr-ng/mL and the mean C_mi_n was 182 ng/mL. Those subjects, when given the 120 mg pseudoephedrine hydrochloride as an experimental formulation, reached a steady-state maximum plasma pseudoephedrine concentration of 365 ng/mL (103% of that of the Reference) 4.10 hours after the last dose (124.10 hours after the first dose, 99.4% of that of the Reference). The mean AUC_SS was 3550 hr- ng/mL (102% of that of the Reference) and the mean C_m;_n was 173 ng/mL.

[0251] The mean plasma concentrations of guaifenesin are depicted in Figure 25. The resulting pharmacokinetic data are shown in Tables 26 through 28. At steady state, the subjects given 1200 mg guaifenesin every 12 hours, as Agent's File Reference: 62808.000021

Reference Mucinex for 11 doses, reached a steady-state maximum plasma guaifenesin concentration of 1960 ± 859 ng/mL (Mean ± Standard Deviation) in 0.81 hours ± 0.305 hour after the last dose (120.81 hours after the first dose) and the steady-state AUC (AUC_SS) was 7209 ± 3746 hr-ng/mL. At steady state, the subjects given 1200 mg guaifenesin every 12 hours, as an experimental tablet formulation for 11 doses, reached a steady-state maximum plasma guaifenesin concentration of 1983 ± 1019 ng/mL (103% ± 29.6% of the Reference Mucinex) in 0.96 hours ± 0.645 hour after the last dose (120.96 hours after the first dose, 100% ± 0.494%). The AUC_SS was 8183 ± 5141 hr-ng/mL (114% ± 27.0%).

Agent's File Reference: 62808.000021

[0252] The mean plasma concentration of Pseudoephedrine are shown in Figure 26. The resulting pharmacokinetic data are shown in Tables 29 through 31. At steady state, the subjects given 120 mg pseudoephedrine hydrochloride, as Sudafed® 12 Hour, every 12 hours for 11 doses, reached a steady-state maximum plasma pseudoephedrine concentration of 361 ± 77.7 ng/mL in 4.89 hours ± 2.14 hour after the last dose (124.89 hours after the first dose). The AUC_SS was 3528 ± 862 hr-ng/mL. At steady state, the subjects given 120 mg pseudoephedrine hydrochloride every 12 hours, as an experimental tablet formulation for 11 doses, reached a steady-state maximum plasma pseudoephedrine concentration of 365 ± 83.3 ng/mL (103% ± 2 1.4% of the Reference Sudafed 12-Hour) in 4.10 hours ± 1.85 hours after the last dose (124.10 hours after the first dose, 99.4% ± 2.09%). The AUC_SS was 3550 ± 898 hr-ng/mL (102% ± 19.6%).

Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0253] In conclusion, the experimental tablet formulation was bioequivalent to the Reference formulations at steady state. The experimental formulation is bioequivalent to the Reference formulations in terms of both C_ma and AUC_SS for guaifenesin and pseudoephedrine hydrochloride. Example 16

[0254] In another study drug interaction potential for combination drugs was examined. The interaction potential for 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride was compared to reference in an open label, single dose, randomized, 3-way crossover study using 36 subjects.

[0255] The subjects were randomized and placed into one of three treatment groups, group A received a 1200 mg controlled release guaifenesin product (Mucinex) with 240 mL of room-temperature water after an overnight fast. Group B received a 120 mg controlled release pseudoephedrine product (Sudafed® 12 Hour) with 240 mL of room-temperature water after an overnight fast. Group C received a 1200 mg guaifenesin product (Mucinex) and 120 mg pseudoephedrine hydrochloride (Sudafed® 12 Hour) with 240 mL of room-temperature water after an overnight fast.

[0256] Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose (the total blood loss for guaifenesin and pseudoephedrine analysis was-450 mL).

[0257] Subjects given 1200 mg of guaifenesin as Mucinex (Treatment A, Reference) reached a O^_x of 2009 ng/mL in 0.89 hours and had an AUCinf of 8138 hr- ng/mL. Subjects given 1200 mg guaifenesin as Mucinex along with 120 mg Pseudoephedrine hydrochloride as Sudafed® 12 Hour (Treatment C, Test) reached a C_maχ of 1989 ng/mL (102% of that of the reference) in 0.84 hour (104% of that of the reference) and had an AUQ_nf of 8052 hr-ng/mL (100% of that of the reference).

[0258] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour (Treatment B, Reference) reached a C_max of 296 ng/mL in 6 hours and had an AUCi_nf of 4505 hr ng/mL. Subjects given 120 mg pseudoephedrine Agent's File Reference: 62808.000021

hydrochloride as Sudafed® 12 Hour, along with 1200 mg guaifenesin as Mucinex (Treatment C, Test) reached a C of 289 ng/mL (98% of that of the reference) in 6 hours (101% of that of the reference) and had an AUQ_nf of 4396 hr-ng/mL (98% of that of the reference). [0259] The plasma concentrations of guaifenesin are depicted in Figure 27. The resulting pharmacokinetic data is shown in Tables 38 through 41. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex (Treatment A, Reference) were 2009 ± 819.2 ng/mL and occurred in 0.89 ± 0.42 hours. The resulting area under the plasma concentration vs. time curve (AUQ_nf was 8138 ± 3253 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex along with 120 mg pseudoephedrine hydrochloride (Treatment C, Test) were 1989 ± 863 ng/mL (102.33% ± 31.40% of that of the reference formulation) and occurred in 0.84 ± 0.31 hours (103.94% ± 35.38% that of the reference formulation). The resulting AUQ_nf was 8052 ± 3344 hr-ng/mL (100.06% ± 18.09% of that of the reference formulation).

Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0260] The plasma concentrations of pseudoephedrine are depicted in Figure 28. The resulting pharmacokinetic data is shown in Tables 42 through 43. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour (Treatment B, Reference) were 295.8 ± 73.25 ng/mL and occurred in 6.17 ± 1.92 hours. The resulting AUQ_nf was 4505 ± 1250 hr- ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour along with 1200 mg guaifenesin as Mucinex (Treatment C, Test) were 289.3 ± 77.61 ng/mL (98.41% ± 12.77% of that of the reference formulation) and occurred in 5.75 ± 1.54 hours (100.74% ± 38.65% of that of the reference formulation). The resulting AUQ_nf was 4396 ± 1347 hr-ng/mL (98.40% ± 15.24% of that of the reference formulation).

Agent's File Reference: 62808.000021

[0261] In conclusion, the pharmacokinetics of guaifenesin and pseudoephedrine hydrochloride are unaffected by the presence or absence of one another. Example 17

[0262] In another experiment the effect of a high-fat on the bioavailability of an of the combination of 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride in normal healthy volunteers was again compared to reference drug in an open-label, single-dose, randomized, 2-way- crossover study using 36 subjects.

[0263] The subjects were randomized and placed into one of two treatment groups. Each treatment group was fasted overnight. Treatment A received an experimental formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water (Reference). Treatment B received an experimental controlled-release formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water, 30 minutes after the beginning of the consumption of a high-fat breakfast (Test).

[0264] Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose (the total blood loss for guaifenesin and pseudoephedrine analysis was 300 mL). Subjects given 1200 mg of guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation following an overnight fast (Treatment A, Reference) reached a plasma guaifenesin C_maχ of 1857 ng/mL in 1.06 hours and had an AUQ_nf of 8142 hr-ng/mL. Subjects given 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation after the consumption of a high-fat meal (Treatment B, Test) reached a plasma guaifenesin C_max of 1364 ng/mL (79.3% of that of the Reference) in 2.06 hour (238% of that of the Reference) and had an AUQ_nf of 7469 hr-ng/mL (94.1% of that of the Reference).

[0265] Subjects given 120 mg pseudoephedrine hydrochloride as an experimental formulation after an overnight fast (Treatment A, Reference) reached a plasma pseudoephedrine C_max of 283 ng/mL in 4.6 hours and had an AUQ_nf of 3746 hr- Agent's File Reference: 62808.000021

ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as an experimental formulation following the consumption of a high-fat meal (Treatment B, Test) reached a plasma pseudoephedrine C_m χ of 301 ng/mL (108% of that of the Reference) in 5.77 hours (137% of that of the Reference) and had an AUQ_nf of 3660 hr-ng/mL (99% of that of the Reference). [0266] The plasma concentrations of guaifenesin are depicted in Figure 29. The resulting pharmacokinetic data are shown in Tables 44 through 46. The maximum plasma concentrations of guaifenesin following 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride after an overnight fast were 1857 ± 838 ng/mL (Mean ± Standard Deviation) and occurred in 1.06 ± 0.582 hours. The resulting area under the plasma concentration vs. time curve (AUQ_nf was 8142 ± 3500 hr-ng/mL. The maximum plasma concentrations of guaifenesin, following 1200 mg oral guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation following the consumption of a high-fat meal (Treatment B, Test), were 1364 ± 691 ng/mL (79.3% ± 34.7% of that of the Reference formulation) and occurred in 2.06 ± 1.16 hours (23 8% ± 157% that of the Reference formulation). The resulting AUQn_f was 7469 ± 3217 hr-ng/mL (94.1% ± 23.1% of that of the Reference formulation).

Agent's File Reference: 62808.000021

[0267] The plasma concentrations of pseudoephedrine are depicted in Figure 45. The resulting pharmacokinetic data are shown in Tables 47 through 49. The maximum plasma concentrations of pseudoephedrine following a 120 mg pseudoephedrine hydrochloride and 1200 mg guaifenesin, in an experimental formulation after an overnight fast (Treatment A, Reference), were 283 ± 79.6 ng/mL and occurred in 4.60 ± 1.56 hours. The resulting AUQ_nf was 3746 ± 997 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following 120 mg pseudoephedrine hydrochloride and 1200 mg guaifenesin, in an experimental formulation following the consumption of a high-fat meal Agent's File Reference: 62808.000021

(Treatment B, Test), were 301 ± 80.4 ng/mL (108% ± 18.5% of that of the Reference formulation) and occurred in 5.77 ± 1.78 hours (137% ± 6 1.9% of that of the Reference formulation). The resulting AUQ_nf was 3660 ± 963 hr- ng/mL (99.0% ± 20.1% of that of the Reference formulation).

Agent's File Reference: 62808.000021

[0268] The rate of absorption of guaifenesin from the experimental formulation, as assessed by C_max is not bioequivalent to the Test formulation in the presence of a high-fat meal. The extent of absorption of guaifenesin from the experimental tablet, as assessed by AUQ_nf, is equivalent to the Test formulation in the presence of a high-fat meal.

[0269] The rate and extent of pseudoephedrine absorption from the experimental formulation was bioequivalent to the Reference formulation in the presence of a high-fat meal.

[0270] In conclusion, the rate of guaifenesin absorption from the experimental formulation is not bioequivalent to the Reference formulation; whereas the extent of guaifenesin absorption is bioequivalent to the Reference formulation in the presence of a high-fat meal. The rate and extent of pseudoephedrine absorption from the experimental formulation are bioequivalent to the Reference formulation in the presence of a high-fat meal. Example 18

[0271] In another experiment the relative bioavailability of guaifenesin and dextromethorphan from an experimental modified release formulation containing both guaifenesin and dextromethorphan was compared to reference guaifenesin and dextromethorphan products in normal volunteers was determined in a 36 subject open-label, randomized, 4-way crossover study. Agent's File Reference: 62808.000021

[0272] The subjects were randomized and placed into one of four treatment groups. Group 1 received an experimental combination tablet containing 1200 mg of controlled-release guaifenesin and 60 mg of controlled-release dextromethorphan hydrobromide (Treatment A) with 240 mL of water, after an overnight fast. Group 2 received a reference controlled-release tablet containing 1200 mg guaifenesin (Mucinex, Treatment B) with 240 mL of water, after an overnight fast. Group 3 received 60 mg of dextromethorphan hydrobromide in a reference immediate-release liquid formulation according to 2 different dosing regimes (one half of the volunteers received 30 mg of dextromethorphan and a second 30 mg dose 6 hours later [Treatment C], while the other half received 20 mg dextromethorphan every 4 hours for three doses [Treatment D]) with 240 mL of water, after an overnight fast. Group 4 received 30 mg of dextromethorphan hydrobromide in a reference immediate-release liquid formulation according to 2 different dosing regimes (one half of the volunteers received 15 mg of dextromethorphan and a second 15 mg dose 6 hours later [Treatment E], while the other half received 10 mg dextromethorphan every 4 hours for three doses [Treatment F]) with 240 mL of water, after an overnight fast. Those subjects that received 30 mg dextromethorphan hydrobromide in one treatment period received 15 mg dextromethorphan in another treatment period; similarly, those that received 20 mg dextromethorphan in one treatment period received 10 mg dextromethorphan in a subsequent treatment period. In this experiment there was a 14-day washout between doses.

[0273] Blood (7 mL, sodium heparin anticoagulant) was obtained at the following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 24, 36, 48, 72 and 96 hours post dose (the total blood loss for guaifenesin and dextromethorphan analysis was to be 644 mL).

[0274] Subjects given 1200 mg of guaifenesin as Mucinex (reference, Treatment B) reached a mean C_maχ of 2145 ng/mL in 0.9 hours and had a mean AUQ_nf of 8953 hr-ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation, also containing 60 mg dextromethorphan hydrobromide (Treatment A), reached Agent's File Reference: 62808.000021

a mean guaifenesin C_max of 2176 ng/mL in 1.4 hours and had a mean AUQ_nf of 8766 hr-ng/mL.

[0275] Subjects given 60 mg dextromethorphan hydrobromide along with 1200 mg guaifenesin in an experimental formulation (Treatment A) reached a mean dextromethorphan C_max of 4834 pg/mL in 5 hours and had a mean AUQ_nf of 68851 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide as 30 mg every 6 hours (Treatment C) reached a mean dextromethorphan C_maχ of 4711 pg/mL in 8.3 hours and had a mean AUQ_nf of 82655 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide as 20 mg every 4 hours (Treatment D) reached a mean dextromethorphan C_max of 3344 pg/mL in 7 hours and had a mean AUQ_nf of 44683 hr-pg/mL. Subjects given 30 mg dextromethorphan hydrobromide as 15 mg every 6 hours (Treatment E) reached a mean dextromethorphan C_max of 2180 pg/mL in 8 hours and had a mean AUQ_nf of 40324 hr-pg/mL. Subjects given 30 mg dextromethorphan hydrobromide as 10 mg every 4 hours (Treatment F) reached a mean dextromethorphan C_maχ of 1286 pg/mL in 7.7 hours and had a mean AUQ_nf of 20114 hr-pg/mL.

[0276] The plasma concentrations of guaifenesin is shown in Figure 33. The resulting pharmacokinetic data is shown in Tables 50 through 52. Subjects given 1200 mg of guaifenesin as Mucinex (Treatment B) reached a mean C_maχ of 2145 ± 997 ng/mL (Mean ± Standard Deviation) in 0.91 ± 0.5 hours and had an AUCi_n of 8953 ± 4272 hr-ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation also containing 60 mg dextromethorphan (Treatment A) reached a mean guaifenesin C_max of 2176 ± 1320 ng/mL (101.36% ± 29.88% of that of Mucinex) in 1.44 ± 0.67 hour (178.57% ± 82.70% of that of Mucinex) and had an AUQ_n of 8761 ± 4755 hr-ng/mL (99.57% ± 24.27% of that of Mucinex). These data indicate that the pharmacokinetics of guaifenesin are not affected by the presence of dextromethorphan. Agent's File Reference: 62808.000021

277] The plasma concentrations of dextromethorphan is shown in Figure 34. The resulting pharmacokinetic data is shown in Tables 53 through 61. Subjects given 60 mg dextromethorphan hydrobromide as an experimental formulation also containing 1200 mg guaifenesin (Treatment A) reached a mean dextromethorphan C_maχ of 4834 ± 6182 pg/mL in 5.06 ± 0.93 hours and had an AUCinf of 68851 ± 112906 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide as 30 mg every 6 hours (Treatment C) reached a mean dextromethorphan C_maχ of 4711 ± 6124 pg/mL (141.85% ± 82.73% of that of the Agent's File Reference: 62808.000021

experimental tablet, Treatment A) in 8.31 ± 1.58 hours (62.07% ± 23.12% of that of Treatment A) and had an AUQ_n of 82655 ± 123509 hr-pg/mL (108% ± 44.44% of that of Treatment A). Subjects given 60 mg dextromethorphan hydrobromide as 20 mg every 4 hours (Treatment D) reached a mean dextromethorphan C_raaχ of 3130 ± 2355 pg/mL (100.31% ± 37.06% of that of the reference) in 7.01 ± 1.93 hours (80.02% ± 22.83% of that of Treatment A) and had an AUQ„_f of 44683 ± 37119 hr-pg/mL (82.77% ± 22.93% of that of Treatment A). These results indicate that the tablet is not bioequivalent to either dextromethorphan dosing regimen, but is equivalent to the range generated by these two dosing regimens. These data also indicate that the pharmacokinetics of dextromethorphan are not affected by the presence of guaifenesin. [0278] Subjects given 30 mg dextromethorphan hydrobromide as 15 mg every 6 hours (Treatment E) reached a mean dextromethorphan C_max of 2180 ± 2650 pg/mL (53.89% ± 17.62% of that of Treatment C) in 8.03 ± 2.52 hours (96.08% ± 24.88% of that of Treatment C) and had an AUQ_nf of 40324 ± 62644 hr- pg/mL (5 1.73% ± 16.77% of that of Treatment C). Subjects given 30 mg dextromethorphan hydrobromide as 10 mg every 4 hours (Treatment F) reached a mean dextromethorphan C_maχ of 1286 ± 903 pg/mL (53.41% ± 12.82% of that of Treatment D) in 7.73 ± 2.43 hours (142.42% ± 67.86% of that of Treatment D) and had an AUQ_nf of 6945 ± 16158 hr-pg/mL (54.32% ± 16.37% of that of Treatment D). These data suggest that the pharmacokinetics of dextromethorphan are linear over the range studied.

Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

Agent's File Reference: 62808.000021

[0279] In conclusion, the pharmacokinetics of guaifenesin and dextromethorphan are not affected by the presence of the other component and the pharmacokinetics of dextromethorphan are linear over the range studied. Example 19

[0280] In another experiment the relative bioavailability of guaifenesin and dextromethorphan from an experimental modified release formulation, containing both guaifenesin and dextromethorphan was compared to reference guaifenesin and dextromethorphan was determined in normal volunteers in a 36 subject open-label, single-dose, randomized, 3-way-crossover study.

[0281] The subjects were randomized and placed into one of three treatment groups. Group 1 received a 1200-mg controlled-release guaifenesin product (Mucinex) plus 60 mg of dextromethorphan hydrobromide (administered as 30 mg every 6 hours), with 240 mL of water after an overnight fast (Reference). Group 2 received a 1200-mg controlled-release guaifenesin product (Mucinex) plus 60 mg of dextromethorphan hydrobromide (administered as 20 mg every 4 hours), with 240 mL of water after an overnight fast (Reference). Group 3 received an experimental controlled-release tablet containing 1200 mg guaifenesin and 60 mg of dextromethorphan hydrobromide, with 240 mL of water after an overnight fast (Test). In this experiment there was a 14-day washout between doses.

[0282] Blood (7 mL sodium heparin anticoagulant) was obtained at the following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 6.5, 6.75, 7, 7.5, 8,

9, 10, 11, 12, 14, 16, 24, 36, 48, 72 and 96 hours post dose (the total blood loss for guaifenesin and dextromethorphan analysis was 609 mL). Subjects given

1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan Agent's File Reference: 62808.000021

hydrobromide as two 30-mg doses 6 hours apart (Treatment A, Reference), reached a mean plasma guaifenesin C_maχ of 1743 ng/mL in 1.25 hours and had an AUCi_nf, of 7836 hr-ng/mL. Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as three 20-mg doses 4 hours apart (Treatment B, Reference), reached a mean plasma guaifenesin C_max of 1783 ng/mL in 1.27 hours and had an AUQ_nf of 7616 hr- ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation, also containing 60 mg dextromethorphan hydrobromide (Treatment C, Test), reached a mean plasma guaifenesin C_max of 1710 ng/mL in 1.55 hour and had an AUQ_nf of 7102 hr-ng/mL.

[0283] Subjects given 1200 mg guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as 30 mg Vick's Formula 44 Cough Medicine and a second 30-mg dextromethorphan hydrobromide dose 6 hours later (Treatment A, Reference), reached a mean plasma dextromethorphan C_maχ of 7946 pg/mL in 8.32 hours and had an AUQ_nf of 294267 hr-pg/mL. Subjects given 1200 mg guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as 20 mg Nick's Formula 44 Cough Medicine, a second 20-mg dextromethorphan hydrobromide dose 4 hours later and a third 20-mg dextromethorphan hydrobromide dose 4 hours after that (Treatment B, Reference), reached a mean plasma dextromethoφhan C_max of 8598 pg/mL in 8.90 hours and had an AUQ_nf of 339447 hr-pg/mL. Subjects given 1200 mg guaifenesin along with 60 mg dextromethorphan hydrobromide in an experimental formulation (Treatment C, Test), reached a mean plasma dextromethorphan C_maχ of 7483 pg/mL in 6.30 hours and had an AUQ_nf of 316592 hr-pg/mL.

[0284] The plasma concentrations of guaifenesin are shown in Figure 35. The resulting pharmacokinetic data are shown in Tables 62 through 64. Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as two 30-mg doses 6 hours apart (Treatment A, Reference), reached a mean plasma guaifenesin C_maχ of 1743 ± 903 ng/mL (Mean ± Standard Deviation) in 1.25 ± 0.660 hours and had an AUQ_nf of 7836 ± 3616 hr-ng/mL.

Il l Agent's File Reference: 62808.000021

Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as three 20-mg doses 4 hours apart (Treatment B, Reference), reached a mean plasma guaifenesin C_maχ of 1783 ± 808 ng/mL in 1.27 ± 0.833 hours and had an AUQ_nf of 7616 ± 3398 hr-ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation, also containing 60 mg dextromethorphan hydrobromide (Treatment C, Test), reached a mean plasma guaifenesin C_maκ of 1710 ± 807 ng/mL in 1.55 ± 0.789 hour and had an AUQ_nf of 7102 ± 2807 hr-ng/mL.

Agent's File Reference: 62808.000021

285] The plasma concentrations of dextromethorphan are shown in Figure 36. The resulting pharmacokinetic data are shown in Tables 65 through 67. Subjects given 1200 mg guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as 30 mg Nick's Formula 44 Cough Medicine and a second 30- mg dextromethorphan hydrobromide dose 6 hours later (Treatment A, Reference), reached a mean plasma dextromethorphan C_maχ of 7946 ± 12386 pg/mL in 8.32 ± 2.88 hours and had an AUQ_nf of 294267 ± 724235 hr-pg/mL. Subjects given 1200 mg guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as 20 mg Nick's Formula 44 Cough Medicine, a second 20-mg dextromethorphan hydrobromide dose 4 hours later and a third 20-mg dextromethorphan hydrobromide dose 4 hours after that (Treatment B, Reference), reached a mean plasma dextromethorphan C_max of 8598 ± 13559 pg/mL in 8.90 ± 3.62 hours and had an AUQ_nf of 339447 ± 850232 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide, along with 1200 mg guaifenesin in an experimental formulation (Treatment C, Test), reached a mean plasma dextromethorphan C_m χ of 7483 ± 12332 pg/mL in 6.30 ± 2.64 hours and had an AUQnf of 316592 ± 796975 hr-pg/mL. Agent's File Reference: 62808.000021

[0286] Dextromethorphan hydrobromide is widely recognized as a highly variable drug and therefore one can consider confidence interval width of 70% to 143% as bioequivalent rather than the classical 80% to 125%. In conclusion, Agent's File Reference: 62808.000021

guaifenesin in the experimental tablet is clearly bioequivalent to that of the Reference, Mucinex, in terms of C_maχ, AUCo-t or AUQ_nf as the 90% confidence intervals are all contained within 80% to 125%. Dextromethorphan hydrobromide in the experimental tablet can be considered bioequivalent to both 30 mg dextromethorphan hydrobromide every 6 hours, and 20 mg every 4 hours, in terms of C_maχ_> AUCo-_t or AUQ_nf as the 90% confidence intervals are contained within 70% to 143%. Example 20

[0287] To determine the relative bioavailability of guaifenesin and dextromethorphan from an experimental modified release formulation containing both guaifenesin and dextromethorphan following the consumption of a high fat meal was compared to following an overnight fast in normal volunteers an open label, single dose, randomized, 2-way crossover study was conducted in 36 subjects.

[0288] The subjects were randomized and placed into one of two treatment groups. Treatment A received a 1200 mg guaifenesin and 60 mg dextromethorphan hydrobromide with 240 mL of water after an overnight fast (Reference). Treatment B received a 1200 mg guaifenesin and dextromethorphan hydrobromide experimental tablet with 240 mL of water within 30 minutes after the beginning of the consumption of a high fat meal (Test). There was a 14 day washout between doses.

[0289] Blood (7 mL, sodium heparin anticoagulant) was obtained at the following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 and 96 hours post dose (the total blood loss for guaifenesin and dextromethorphan analysis will be 280 mL). Subjects given 1200 mg of guaifenesin and 60 mg dextromethorphan hydrobromide in an experimental formulation following an overnight fast (Treatment A, Reference) reached a mean C_ma of 2030 ng/mL in 1.61 hours and had an AUQ_nf of 8128 hr-ng/mL. Subjects given 1200 mg of guaifenesin and 60 mg dextromethorphan hydrobromide following the consumption of a high fat meal (Treatment B, Test) reached a mean C_maχ of 1825 ng/mL (98.0% of that of Treatment A) in 2.93 Agent's File Reference: 62808.000021

hours (248% of that of Treatment A) and had an AUQ_nf of 7093 hr-ng/mL (92.9% of that of Treatment A).

[0290] Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin in an experimental formulation following an overnight fast (Treatment A, Reference) reached a mean dextromethorphan C_maχ of 10722 pg/mL in 6.23 hours and had an AUQ_nf of 466518 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin in an experimental formulation after the consumption of a high fat meal (Treatment B, Test) reached a mean dextromethorphan C_maχ of 12757 pg/mL (132% of that of Treatment A) in 5.74 hours (104% of that of Treatment A) and had an AUQ_nf of 472064 hr-pg/mL (117% of that of Treatment A).

[0291] The plasma concentrations of guaifenesin is shown in Figure 37. The resulting pharmacokinetic data is shown in Tables 68 through 70. Subjects given 1200 mg of guaifenesin and 60 mg dextromethorphan hydrobromide in an experimental formulation following an overnight fast (Treatment A, Reference) reached a mean C_m χ of 2030 ± 882 ng/mL (Mean ± Standard Deviation) in 1.61 ± 1.15 hours and had an AUQ_nf of 8128 ± 3497 hr-ng/mL. Subjects given 1200 mg of guaifenesin and 60 mg dextromethorphan hydrobromide in an experimental formulation after the consumption of a high fat meal (Treatment B, Test) reached a mean C_maχ of 1825 ± 789 ng/mL (98.0% ± 40.3% of that of Treatment A) in 2.93 ± 1.44 hours (248% ± 164% of that of Treatment A) and had an AUQ_nf of 7093 ± 2787 hr-ng/mL (92.9% ± 23.6% of that of Treatment A).

Agent's File Reference: 62808.000021

[0292] The plasma concentrations of dextromethorphan is shown in Figure 38. The resulting pharmacokinetic data is shown in Tables 71 to 73. Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin in an experimental formulation following an overnight fast (Treatment A, Reference) reached a mean dextromethorphan C_maχ of 10722 ± 15966 pg/mL in 6.23 ± 3.55 hours and had an AUQ_nf of 466518 ± 987204 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin in an experimental formulation after the consumption of a high fat meal (Treatment B, Test) reached a mean dextromethorphan C_maχ of 12757 ± 17914 pg/mL (132% ± 69.8% of that of Treatment A) in 5.74 ± 2.27 hours (104% ± 43.4% of that of Treatment A) and had an AUQ_nf of 472064 ± 977485 hr-pg/mL (117% ± 61.5% of that of Treatment A). Agent's File Reference: 62808.000021

[0293] In conclusion, there is no food effect on the absorption of guaifenesin from the experimental tablet. There is an effect of food on the rate of absorption of dextromethorphan from the experimental tablet formulation (a small increase in the rate of absorption) but not on the extent of absorption. Example 21

[0294] To determine the relative bioavailability of guaifenesin and dextromethorphan from an experimental modified release formulation containing both guaifenesin and dextromethorphan was compared to reference guaifenesin and dextromethorphan products in normal volunteers an open-label, multiple- dose, randomized, 3-way-crossover study was conducted in 36 subjects. Agent's File Reference: 62808.000021

[0295] The subjects were randomized and placed into one of three treatment groups. Group 1 received a 1200-mg controlled-release guaifenesin product (Mucinex) plus 60 mg of dextromethorphan hydrobromide (administered as 30 mg every 6 hours) with 240 mL of water after an overnight fast, and again 12 hours later for 11 twelve-hour dosing periods (Treatment A, Reference). Group 2 received a 1200-mg controlled-release guaifenesin product (Mucinex) plus 60 mg of dextromethorphan hydrobromide (administered as 20 mg every 4 hours) with 240 mL of water after an overnight fast, and again 12 hours later for 11 twelve- hour dosing periods (Treatment B, Reference). Group 3 received an experimental controlled-release tablet containing 1200 mg guaifenesin and 60 mg of dextromethorphan hydrobromide with 240 mL of water after an overnight fast, and again 12 hours later for 11 twelve-hour dosing periods (Treatment C, Test). There was a 14-day washout between doses.

[0296] Blood (7 mL, sodium heparin anticoagulant) was obtained at the following times: Day 1 Pre-AM dose, Day 4 Pre-AM dose and Day 5 Pre-AM dose for all three treatment groups. On Day 6 Treatment A subjects were bled at: Pre-Dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 6.5, 6.75, 7, 7.5, 8, 9, 10, 11, 12, 14, 16, 24, 36, 48, 72, and 96 hours post dose. Treatment B subjects were bled at: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, 24, 36, 48, 72 and 96 hours post dose. On Day 6, Treatment C subjects were bled at: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 and 96 hours post dose (the total blood loss for guaifenesin and dextromethorphan analysis was 588 mL).

[0297] Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as two 30-mg doses 6 hours apart (Treatment

A, Reference), reached a mean steady-state plasma guaifenesin C_maχ of 1935 ng/mL in 1.27 hours after the last dose (121 hours after the first dose); had a C_mi_n of 75.5 ng/mL, a C_AVE of 631 ng/mL and an AUCs_te_ad state of 7540 hr-ng/mL. Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as three 20-mg doses 4 hours apart (Treatment

B, Reference), reached a mean steady-state plasma guaifenesin C_maχ of 1938 Agent's File Reference: 62808.000021

ng/mL in 0.850 hours after the last dose (121 hours after the first dose), had a Cmin of 59.6 ng/mL, a C_AVE of 618 ng/mL and an AUCsteady state of 7403 hr- ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation, also containing 60 mg dextromethorphan hydrobromide (Treatment C, Test), reached a mean steady- state plasma guaifenesin C_maχ of 1780 ng/mL in 1.35 hours after the last dose (121 hours after the first dose), had a C_mi_n of 18.2 ng/mL, a C_AVE of 601 ng/mL and an AUCsteady state of 7138 hr-ng/mL.

[0298] Subjects given 60 mg dextromethorphan hydrobromide as 30 mg Nick's Formula 44 Cough Medicine along with 1200 mg guaifenesin as Mucinex and a second 30-mg dextromethorphan. hydrobromide dose 6 hours later (Treatment A, Reference), reached a mean steady-state plasma dextromethorphan C_maχ of 17960 pg/mL in 5.03 hours after the last dose (125 hours after the first dose), had a Cmin of 11949 pg/mL, a C_AVE of 15167 pg/mL and an AUCsteady state of 181904 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide as three 20- mg doses of Nick's Formula 44 Cough Medicine four hours apart, along with 1200 mg of guaifenesin as Mucinex (Treatment B, Reference), reached a mean steady-state plasma dextromethoφhan C_maχ of 17251 pg/mL in 5.91 hours after the last dose (126 hours after the first dose), had a C_min of 11018 pg/mL, a C_AVE of 14097 pg/mL and an AUCsteady state of 169160 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin as an experimental formulation (Treatment C, Test), reached a mean steady-state plasma dextromethorphan C_max of 17213 pg/mL in 5.10 hours after the last dose (125 hours after the first dose), had a C_mi_n of 10978 pg/mL, a C_AVE of 14609 pg/mL and an AUCsteady state of 175309 hr-pg/mL.

[0299] The plasma concentrations of guaifenesin are shown in figures 39 and 40. The resulting pharmacokinetic data are shown in Tables 74 through 76. Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as two 30-mg doses 6 hours apart (Treatment A, Reference), reached a mean steady-state plasma guaifenesin C_maχ of 1935 ± 746 ng/mL at 121 ± 0.854 hours after the first dose (1.27 hours after the last dose), had a C_min of 75.5 ± 73.9 ng/mL, a C_AVE of 631 ± 212 ng/mL and an AUC_Stead_y state of 7540 ± Agent's File Reference: 62808.000021

2570 hr-ng/mL. Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan hydrobromide as three 20-mg doses 4 hours apart (Treatment B, Reference), reached a mean steady-state plasma guaifenesin C_maχ of 1938 ± 637 ng/mL at 121 ± 0.463 hours after the first dose (0.850 hours after the last dose), had a C_mi_n of 59.6 ± 51.9 ng/mL, a C_AVE of 618 ± 205 ng/mL and an AUCs_teady sta_te of 7403 ± 2474 hr-ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation, also containing 60 mg dextromethorphan hydrobromide (Treatment C, Test), reached a mean steady-state plasma guaifenesin C_maχ of 1780 ± 633 ng/mL at 121 ± 0.864 hours after the first dose (1.35 hours after the last dose), had a C_min of 18.2 ± 18.3 ng/mL, a C_AVE of 601 ± 189 ng/mL and an AUCsteady state of 7138 ± 2268 hr-ng/mL.

Agent's File Reference: 62808.000021

[0300] The plasma concentrations of dextromethorphan are shown in figures 41 and 42. The resulting pharmacokinetic data are shown in Tables 77 through 79. Subjects given 60 mg dextromethorphan hydrobromide as 30 mg Nick's Formula 44 Cough Medicine, along with 1200 mg guaifenesin as Mucinex and a second 30-mg dextromethorphan hydrobromide dose 6 hours later (Treatment A, Reference), reached a mean steady-state plasma dextromethorphan C_max of 17960 ± 37537 pg/mL at 125 ± 2.94 hours after the first dose (5.03 hours after the last dose), had a C_min of 11949 ± 28101 pg/mL, a C_AVE of 15167 ± 33349 pg/mL and an AUCsteady st_ate of 181904 ± 400226 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide as three 20-mg doses of Vick's Formula 44 Cough Medicine 4 hours apart, along with 1200 mg of guaifenesin as Mucinex (Treatment B, Reference), reached a mean steady-state plasma dextromethorphan C_max of 17251 ± 39562 pg/mL, at 126 ± 1.73 hours after the first dose (5.91 hours after the last dose), had a C_mj_n of 11018 ± 26007 pg/mL, a C_AVE of 14097± 33537 pg/mL and an AUCst_eady st_at_e of 169160±402449 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin as an experimental formulation (Treatment C, Test), reached a mean steady-state plasma dextromethorphan C_max of 17213 ± 33703 pg/mL at 125 ± 1.62 hours (5.10 hours after the last dose), had a C_mi_n of 10978 ± 24713 pg/mL, a C_AVE of 14609 ± 30804 pg/mL and an AUC_Ste_ady sta_te of 175309 ± 369653 hr-pg/mL. Agent's File Reference: 62808.000021

[0301] In conclusion, guaifenesin in the experimental tablet is bioequivalent to that of the Reference, Mucinex, in terms of C_max and AUC_SS, as the 90% confidence Agent's File Reference: 62808.000021

intervals are all contained within 80% to 125%. Dextromethorphan hydrobromide in the experimental tablet is bioequivalent to both 30 mg dextromethorphan hydrobromide every 6 hours, and 20 mg every 4 hours, in terms of C_m χ and AUC_SS, as the 90% confidence intervals are contained within 80% to 125%. 2] Other embodiments and uses of the invention will be apparent to those of skill in the art from consideration of the specification and practice of the invention disclosed herein. The specification and examples should be considered exemplary only with the true scope and spirit of the invention indicated by the following claims. As will be easily understood by those of skill in the art, variations and modifications of each of the disclosed embodiments can be easily made within the scope of this invention as defined by the following claims.

Claims

Agent's File Reference: 62808.000021CLAIMSWhat is claimed is:

1. A drug delivery system in which a unit dose form comprises a sustained release portion comprising guaifenesin, and optionally a second drug and a release-delaying matrix comprising a hydrophilic polymer and a water- insoluble polymer; an immediate release portion comprising guaifenesin; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours following a single dose.

2. The drug delivery system of claim 1, wherem said optional drug is selected from dextromethoφhan and pseudoephedrine.

3. The drug delivery system of claim 2, wherein said optional drug is only in the sustained release portion.

4. The drug delivery system of claim 2, wherein said optional drug is only in the immediate release portion.

5. The drug delivery system of claim 2, wherein said optional drug is in both the immediate release portion and the sustained release portion.

6. The system of claim 2, wherein the release-delaying matrix comprises hydrophilic polymer and water-insoluble polymer in a weight ratio selected from 1:1 to about 9:1, 3:2 to about 6:1, and 2:1 to about 4:1.

7. The system of claim 2, wherein the total amount of guaifenesin is between 500 mg and 1300 mg.

8. The drug delivery system of claim 7, wherein the total quantity of guaifenesin in said unit dose form is from about 600 mg to about 1200 mg.

9. The system of claim 8, wherein said unit dose form has a C_max for guaifenesin that is bioequivalent to the FDA-specified C_maχ for an immediate guaifenesin release tablet of one-third the dose strength.

10. The system of claim 9, wherein said unit dose form contains 1200 mg of guaifenesin.

11. The system of claim 10, wherein the C_maχ for guaifenesin is selected from between 1,000 ng/mL and 3,750 ng/mL, 1,200 ng/mL and 3,500 ng/mL, 1,350 ng/mL and 3,000 ng/mL, and 1450 ng/mL and 2,750 ng mL. Agent's File Reference: 62808.000021

12. The system of claim 9, wherein said unit dose form contains 600 mg of guaifenesin.

13. The system of claim 12, wherein the C_max for guaifenesin is selected from between 320 ng/mL and 1875 ng/mL, 400 ng/mL and 1500 ng/mL, 500 ng/mL and 1375 ng/mL, and 625 ng/mL and 1250 ng/mL.

14. The system of claim 8, wherein said therapeutically effective level is measured according to C_mi_n.

15. The system of claim 14, wherein the unit dose form has a C_mi_n for guaifenesin that is bioequivalent to the FDA-specified C_mhι for an immediate release guaifenesin tablet containing 400 mg of guaifenesin.

16. The system of claim 14, wherein the C_mi_n for guaifenesin is selected from between 35 ng/mL and 75 ng/mL, 40 ng/mL and 70 ng/mL, 45 ng/mL and 65 ng/mL, and 50 ng/mL and 60 ng/mL.

17. The system of claim 8, wherein said therapeutically effective level is measured according to AUCinf.

18. The system of claim 17, wherein said unit dose form contains 1200 mg of guaifenesin.

19. The system of claim 18, wherein the AUQ_nf for guaifenesin is selected from between 4,000 hr-ng/mL and 12,500 hr-ng/mL, 5,000 hr-ng/mL and 10,000 hr-ng/mL, 5,500 hr-ng/mL and 9,500 hr-ng/mL, and 6,000 hr-ng/mL and 9,000 hr-ng/mL.

20. The system of claim 8, where said unit dose form contains 600 mg of guaifenesin.

21. The system of claim 20, wherein the AUQ_nf for guaifenesin is selected from between 2,000 hr-ng/mL and 6,250 hr-ng/mL, 2,500 hr-ng/mL and 5,000 hr- ng/mL, 2,250 hr-ng mL and 4,750 hr-ng/mL, and 3,000 hr-ng/mL and 4,500 hr-ng/mL.

22. The drug delivery system of claim 2, wherein the immediate release portion further comprises microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. Agent's File Reference: 62808.000021

23. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the dextromethoφhan is from about 1:1 to about 30:1 by weight.

24. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the dextromethoφhan is from about 8:1 to about 12:1 by weight.

25. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the pseudoephedrine is from about 1:1 to about 30:1 by weight.

26. The drug delivery system of claim 2, wherein the ratio of the total quantity of guaifenesin to the pseudoephedrine is from about 8:1 to about 12:1 by weight.

27. The drug delivery system of claim 1, wherein the ratio of the immediate release quantity of guaifenesin to the sustained release quantity of guaifenesin is about 1:1 to about 1:15 by weight.

28. The drug delivery system of claim 1, wherem the ratio of the immediate release quantity of guaifenesin to the sustained release quantity of guaifenesin is from about 2:3 to about 1:11.

29. The drug delivery system of claim 1, wherein at least about 60% of the guaifenesin particles used to make the unit dose form have a particle size in the range of from about 150 μm to 2.0 mm.

30. The drug delivery system of claim 1, wherein a unit dose form has a C_max for guaifenesin of at least about 1900 ng/ml and an AUQ_nf for guaifenesin of at least 7000 hr-ng/ml.

31. The drug delivery system of claim 1, wherein a unit dose form has a C_maχ for guaifenesin of at least 1000 ng ml and an AUQ_nf for guaifenesin of at least 3500 hr-ng/ml.

32. The drug delivery system of claim 1, wherein a unit dose form has a half life of at least 3 hours as determined by serum analysis.

33. The drug delivery system of claim 1, wherein the sustained release portion comprises about 75% to about 95% by weight of guaifenesin, from about 1% Agent's File Reference: 62808.000021

to about 15% of dextromethoφhan, from about 0.5% to about 10% of the hydrophilic polymer, and about 0.5% to about 2.5% water-insoluble polymer by weight.

34. The drug delivery system of claim 1, wherein the unit dose form comprises immediate release and sustained release portions each comprise abutting substantially planar layers which form a bi-layer tablet.

35. The drug delivery system of claim 1, wherein the dextromethoφhan is bioavailable at therapeutically effective level for at least twelve hours following a single dose.

36. The drug delivery system of claim 1, wherein the sustained release portion comprises from about 75% to 80% by weight of guaifenesin, from about 5% to about 10%) by weight of dextromethoφhan, from about 3% to about 6% of the hydroxypropyl cellulose, and from about 1% to about 1.5% by weight of an acrylic resin.

37. The drug delivery system of claim 1, wherein a unit dose form has a C_max for guaifenesin from about 1600 to 2500 ng/ml and an AUQ_nf for guaifenesin of about 5600 to 8750 hr-ng/ml.

38. The drug delivery system of claim 1, wherein a unit dose form has a C_max for guaifenesin of about 800 to 1250 ng/ml and an AUQ_nf for guaifenesin of about 2800 to 4375 hr-ng/ml.

39. The drug delivery system of claim 1, wherein the unit dose form comprises a capsule that contains discrete or associated immediate release and sustained release portions.

40. The drug delivery system of claim 7, which is approximately equally effective when administered to a patient on an empty or full stomach.

41. The drug delivery system of claim 7, wherein said unit dose form has the guaifenesin serum concentration profile of Figure 10.

42. A drug product comprising an immediate release portion comprising a guaifenesin and optionally a second drug wherein guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising guaifenesin and a second drug Agent's File Reference: 62808.000021

wherein the ratio of the immediate release guaifenesin to the sustained release guaifenesin is about 1 :1 to about 1 :15, the product provides a guaifenesin C_max in a human subject equivalent to the C_maχ obtained when the first of three doses of a FDA-specified immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and the product provides a therapeutically effective bioavailable guaifenesin for at least twelve hours after a single dose in a human subject according to serum analysis.

43. The drug product of claim 42, wherem the second drug is selected from dextromethoφhan and pseudoephedrine.

44. The drug product according to claim 43, wherein the immediate release and sustained release portions each comprise abutting substantially planar layers which form a bi-layer tablet.

45. The drug product according to claim 43, wherein the sustained release portion is coated by a layer of the immediate release portion.

46. The drug product according to claim 43, wherein the product comprises a capsule containing immediate release and sustained release portions.

47. A method of treating a subject in need of temporary relief from bronchial mucus accumulation comprising administering to said subject a therapeutically effective amount of one drug delivery system according to claim 2.

48. The method according to claim 47, wherein the drug delivery system is administered orally.

49. A method of treating a subject in need of temporary relief from bronchial mucus and coughing comprising administering to said subject a therapeutically effective amount of a modified release drug product comprising guaifenesin and dextromethoφhan in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising a guaifenesin, dextromethoφhan and a release-delaying matrix, Agent's File Reference: 62808.000021

wherein the release-delaying matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of hydrophilic polymer to water-insoluble polymer from about 1:1 to about 9:1, wherein the guaifenesin has a C_max in a human subject equivalent to the C_max obtained when the first of three doses of a FDA-specified immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and releases therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in a human subject according to serum analysis.

50. A method of treating a subject in need of temporary relief from bronchial mucus and nasal congestion comprising administering to said subject a therapeutically effective amount of a modified release drug product comprising guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in the subject's stomach; and a sustained release portion comprising a guaifenesin, pseudoephedrine and a release- delaying matrix, wherein the release-delaying matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of hydrophilic polymer to water-insoluble polymer from about 1:1 to about 9:1, wherein the guaifenesin has a C_maχ in a human subject equivalent to the Cma obtained when the first of three doses of a FDA-specified immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and releases therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in a human subject according to serum analysis.

51. A drug delivery system comprising a sustained release portion comprising guaifenesin, dextromethoφhan and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; and an immediate release portion comprising guaifenesin and dextromethoφhan; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours according to serum analysis following a single dose and Agent's File Reference: 62808.000021

wherein a unit dose form demonstrates a C_max in a human subject above 640 ng/ml with a T_max within .8 hours and maintains a C_mιn above 80 ng/ml for a period of 12 or more hours.

52. A drug delivery system comprising a sustained release portion comprising guaifenesin, pseudoephedrine and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; and an immediate release portion comprising guaifenesin; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours according to serum analysis following a single dose and wherein a unit dose form demonstrates a C_max in a human subject above 640 ng/ml with a T_max within .8 hours and maintains a C_mm above 80 ng/ml for a period of 12 or more hours.

53. A drug delivery system in which a unit dose form comprises a sustained release portion comprising guaifenesin, pseudoephedrine and a release- delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; an immediate release portion comprising guaifenesin; wherein the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours following a single dose.

54. A drug delivery system in which a unit dose form comprises a sustained release portion comprising guaifenesin, dextromethoφhan and a release- delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer; an immediate release portion comprising guaifenesin and dextromethoφhan; wherem the guaifenesin is bioavailable at a therapeutically effective level for at least twelve hours following a single dose.