EA007156B1 - Sustained release of guaifenesin combination drugs - Google Patents

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

The invention describes a modified, slow-release composition for oral administration, comprising combinations of guaifenesin and optionally at least one additional drug and methods for its preparation. In particular, the invention describes a delayed release composition that provides a therapeutically effective plasma concentration of guaifenesin and an optional additional drug for approximately 12 hours. The invention further describes combinations that provide a maximum plasma concentration equivalent to the plasma concentration that is achieved upon immediate release from the tablet drug to maintain a therapeutically effective plasma concentration for approximately 12 hours

Slow-release pharmaceutical compositions provide a significant advantage over immediate-release compositions to both clinicians and their patients. Slow-release dosage forms are designed for fewer daily doses than their immediate-release counterparts. For example, a standard dosage regimen for an immediate-release drug of 400 mg with such a short half-life as that of guaifenesin requires administration three times within 12 hours to ensure adequate bioaccumulation and the desired therapeutic effect. This leads to a series of three plasma concentrations in the patient, showing a rapid increase and an equally rapid subsequent decrease in drug concentration. As a result, patients have only a short range of plasma concentrations of the drug, which corresponds to the plasma concentration for optimal therapy. On the other hand, to achieve a therapeutic effect, a slow-release dosage form of 1200 mg requires a single dose every 12 hours. In general, a slow-release dosage form allows you to adjust the absorption rate of the drug and avoid excessive absorption while maintaining an effective plasma concentration of the drug to ensure Patient stable therapeutic effect for a longer time.

In addition to reducing the frequency of dosing and providing a more stable therapeutic effect, slow-release dosage forms help to reduce the side effects caused by the drug. Since the slow-release dosage forms release the drug gradually, in increasing quantities, in contrast to the high and low cyclic concentrations in the case of immediate-release compositions, the patient's body absorbs the drug more easily and thus avoids undesirable side effects. For patients who are self-medicating, slow-release dosage forms are generally of great convenience because of the lower dosage frequency, the smaller amounts of dosage units to be taken, and because of the reduction in undesired side effects.

In general, slow release compositions contain drug particles mixed with or coated with a polymer material or a mixture of materials that do not decompose or decompose in the stomach and / or intestines over a period of time. The release of the drug can occur by absorption, erosion, destruction, diffusion, or the like, depending on the nature of the polymer material or the mixture of polymers used.

Traditionally, pharmaceutical manufacturers have used hydrophilic hydrocolloid gelling polymers such as hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose is widely used and also known as hypromellose), hydroxypropyl cellulose or Pullulan to prepare slow-release tablets or capsules. These polymers, when exposed to an aqueous medium with a low pH value, first form a gel, which ensures slow diffusion of the active drug that is contained in the polymer matrix. When a gel enters an environment with a higher pH, for example, in the intestine, it dissolves, resulting in less controlled release of the drug. Some pharmaceutical manufacturers use polymers such as acrylic resins, acrylic latex dispersions, cellulose acetate phthalate and hydroxypropyl methylcellulose phthalate, or combinations thereof with hydrophilic polymers that dissolve only at high pH, to improve the sustained release process under high pH conditions.

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In general, these compositions are prepared by combining a medicament with a finely divided powder of a hydrophilic polymer or hydrophilic and water insoluble polymers. These components are mixed and granulated with water or an organic solvent; then the granules are dried. Next, the dry granules are usually mixed with various pharmaceutical additives and compressed into tablets.

Although compositions of this type have been successfully used to prepare dosage forms having a sustained release property, these compositions, over a longer period of time, generally do not provide the desired release profile or the desired plasma concentration of the drug. These slow release compositions are typically characterized in that the drug appears late in the blood stream and, accordingly, the therapeutic effect is delayed. In addition, when the drug does appear, its maximum plasma concentration (C _max ) is lower than the maximum concentration required for the most optimal therapeutic effect. In addition, most compositions that claim to have a twelve-hour sustained release potential for a drug release almost all of the amount of drug contained within 6-8 hours, making the composition less therapeutically effective by the end of the twelve-hour period. To prevent the plasma concentrations of the drug from falling below the therapeutically effective level (C _min ) over longer periods of time, many manufacturers increase the strength of the dosage form. However, an increase in the strength of the drug is accompanied by an increase in side effects.

Other pharmaceutical manufacturers have made tablets and capsules containing a combination of an immediate release composition and a slow release composition to improve the release profile of some slow release compositions. Although this solution in the case of some compositions improves C _max and the length of time during which the drug appears in the blood stream, however, the extended therapeutic effect does not improve.

In addition, drugs have different solubilities and pH dependencies, which affect the rate of dissolution and bioaccumulation. Bioaccumulation can also be influenced by many factors, for example, the amount and type of excipients used, the granulation process, the pressing force (in the manufacture of the tablet), available when dissolved by surface area and external factors such as mixing in the stomach and the presence or absence of food. Due to these many factors, in the preparation of prolonged solid dosage forms, in particular solid dosage forms, providing appropriate bioaccumulation and optimal therapeutic effect, specific compositions play an important role.

Guaifenesin, 3- (2-methoxyphenoxy) -1,2-propanediol, is an expectorant that increases the amount of liquid secretions in the airways and helps relieve phlegm. Reducing the viscosity of fluid secretions, guaifenesin increases the effectiveness of the cough reflex and ciliary action when removing the accumulated fluid mass from the trachea and bronchi. Guaifenesin is easily absorbed by the intestinal tract, quickly absorbed and excreted in the urine. Guaifenesin has a characteristic half-life of metabolism lasting approximately 1 hour. When using the immediately releasing composition, rapid metabolism and the release of guaifenesin provide only a short interval of therapeutic efficacy.

Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and affects the nasal mucosa as a decongestant. Pseudoephedrine exhibits peripheral effects that are similar to the effects of ephedrine and central effects that are similar to the effects of amphetamines, but less intense. Therefore, it has the potential against stimulant effects. At the recommended oral dose in adults with normal blood pressure, it exhibits a weak or zero pressor effect. It was found that the average half-life for pseudoephedrine is 4-6 hours.

Dextromethorphan acts centrally, raising the threshold of coughing. It does not exhibit any painkiller or addictive properties. The main circulating metabolite is dextrorphan.

There is a need for both sustained release dosage forms of guaifenesin and combinations thereof that are capable of delaying the release of therapeutically effective amounts of a drug over longer periods of time. In addition, there is a need for sustained release dosage forms of guaifenesin and combinations thereof that result in a C _max equivalent to C _max for immediate release formulations and which appear in the blood stream as quickly as immediate release formulations, while maintaining a therapeutic effect.

SUMMARY OF THE INVENTION

The invention relates to strategies and projects for compositions with modified release of guaifenesin and combined dosage forms of guaifenesin. This invention describes a sustained release composition comprising guaifenesin and at least one additional drug. Slow-release composition (8B) may include

- 2,007156 a combination of at least one hydrophilic polymer and at least one water-insoluble polymer. The total weight ratio of the hydrophilic polymer to the water insoluble polymer may be in the range of about 1: 1 (one to one) to 9: 1 (nine to one), more preferably in the range of about 3: 2 (three to two) to 6: 1 (six to one) and most preferably in the range of about 2: 1 (two to one) to 4: 1 (four to one). When a tablet containing a slow release composition enters an aqueous medium with a low pH, such as a medium in the stomach, the guaifenesin and other drug contained in them diffuse from the gels of the combined polymers). When the tablet passes through the intestines, where the pH of the aqueous medium is higher, the gel begins to dissolve, while releasing guaifenesin and / or other drugs) in controlled amounts. A tablet is capable of releasing therapeutically effective amounts of guaifenesin in a given period, for example, for twelve or more hours, and at least one additional drug, immediately or over a certain longer period.

This invention also encompasses a modified release composition that includes two parts (e.g., a double-layer tablet or capsule), an immediate release composition (ΙΒ) and a slow release composition (8H). Each composition includes a certain amount of guaifenesin and may optionally contain at least one additional drug. The immediate release composition is formulated to dissolve in an acidic aqueous medium such as that in the stomach, quickly release the guaifenesin contained within the specified portion, and randomly release at least one additional drug. The delayed release portion may comprise a combination of a hydrophilic polymer and a water-insoluble polymer in the range of about 1: 1 (one to one) to 9: 1 (nine to one), more preferably in the range of about 3: 2 (three to two) - 6: 1 (six to one) and most preferably in the range of a ratio of approximately 2: 1 (two to one) to 4: 1 (four to one). The delayed release portion may also contain additional drug (s).

The invention also relates to slow release compositions of the type described above in the form of capsules having beads or granules, both of the immediate release composition or both of the slow release composition. The beads may include a mixture of discrete beads, each of which may include only one of 8B or ΙΚ compositions, or may include beads containing both 8B and ΙΚ compositions combined in one bead, or combinations thereof. Alternatively, a single-tablet, sustained release composition may include a core that is coated with a layer of an immediate release composition. For illustrative purposes, the invention will be described in detail with an example implementation of a two-layer tablet. It should be borne in mind that in the case of an immediately releasing composition and / or a delayed releasing composition, guaifenesin and an optional additional drug can be mixed within the same matrix part, or both drugs can be prepared as separate drug-releasing parts, which further will be compressed under pressure or mixed to make capsules (for example, capsules containing individual beads or granules), etc.

The two-layer tablet shows the maximum plasma concentration (C _max ) and the duration of presence in the blood stream, which are equivalent to the corresponding parameters for immediate-release tablets. The two-layer tablet also provides a sustained release of guaifenesin in approximately a twelve-hour period from a single dose. In addition, a two-layer tablet maintains plasma levels of guaifenesin for a period of approximately 12 hours without increasing dosage intensity. Since a bilayer tablet may also contain at least one additional drug, the additional drug can be formulated within the slow release composition, the immediate release composition, or both. In one embodiment, the bilayer tablet maintains the plasma concentration levels of at least one additional drug at a therapeutically effective level for a period of about 12 hours, without increasing dosage intensity.

In another embodiment, the tablets and capsules of the present invention provide C _minutes for 10 hours, more preferably for 12 or more hours, i.e. above the required therapeutically effective level. In a more preferred embodiment, the tablet or capsule of the present invention provides the aforementioned C _min parameters and provides the necessary Smake to mimic an immediate-release product and to alleviate the symptom. In a more preferred embodiment, the drug delivery system provides the aforementioned Cmin parameters and provides the necessary Max to mimic an immediate release product and achieve symptom relief within a substantially the same T _max period as in the case of an immediate release profile composition.

In another embodiment of the invention, the drug delivery system provides Max, which does not result in an equivalent for the immediate-releasing Max, but

- 3 007156 does provide C _max , which is therapeutically effective to revitalize the system and reduce the likelihood of side effects due to increased C _max .

The invention also relates to methods for the preparation of slow release compositions and two-layer tablets. An example of a method for preparing a sustained release composition includes: mixing a hydrophilic polymer and active ingredients in a mixer; adding water to the mixture and mixing it for a long time; crumbling and drying of the mixture in order to obtain granules enclosed in a hydrophilic polymer; grinding and sieving the obtained granules and mixing them with various pharmaceutical additives, with an additional hydrophilic polymer and a water-insoluble polymer. After that, the composition can be tabletted, and then coated with a protective film that quickly dissolves or breaks down under the influence of gastric juice.

An example of a method for preparing a two-layer tablet includes mixing a certain amount of guaifenesin and optionally at least one drug with various excipients, colorants and / or other pharmaceutical additives to obtain an immediate-release composition; mixing another amount 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 obtain a slow-release composition; and compressing a certain amount of the immediate-release composition with a certain amount of the slow-release composition to form a two-layer tablet. Further, the tablet may optionally be coated with a protective film that quickly dissolves or disintegrates under the influence of gastric juice.

Other objectives, advantages, and implementations of the present invention, which are described below, will be apparent from this description and the corresponding methods of carrying out the invention.

Brief Description of the Drawings

FIG. 1 is a flow diagram and shows the steps of a wet granulation method in preparing a slow release composition;

FIG. 2 is a flow diagram and shows the steps of a dry granulation process in the preparation of a slow release composition;

FIG. 3 is a flow diagram and shows steps of a method for preparing a two-layer tablet;

FIG. 4 is a diagram showing dissolution profiles of tablets comprising two different sustained release formulations;

FIG. 5 is a diagram illustrating dissolution profiles of a commercially available dosage form and two sustained release dosage forms of guaifenesin;

FIG. 6 is a diagram showing the plasma concentration of guaifenesin after a certain time in healthy volunteers who were dosed with guaifenesin in three different compositions: immediately releasing a commercially available composition and two different delayed-releasing compositions (LO1 7B-32 and LO1 7B-31);

FIG. 7 is a diagram showing the plasma concentration of guaifenesin in healthy volunteers after a certain time interval after taking a commercially available immediate release tablet, a non-layered modified tablet of the present invention, and two two-layer modified release tablets of the present invention (one containing 600 mg of the immediate releasing composition and 600 mg of a slow-release composition, and another, including 400 mg of an immediate-release composition and 800 mg of a slow-release releasing composition);

FIG. 8 is a diagram illustrating dissolution profiles of four sustained release tablets: the first non-layered tablet includes 1200 mg of a sustained release composition; the second tablet is two-layer, includes 600 mg of a slow-release composition and 600 mg of an immediate-release composition; a third two-layer tablet includes 800 mg of a slow-release composition and 400 mg of an immediate-release composition; and the fourth tablet is two-layer and includes 1000 mg of a slow-release composition and 200 mg of an immediate-release composition;

FIG. 9 is a graph showing the plasma concentration of guaifenesin over an average 12-hour interval (from 11 twelve-hour intervals over 5.5 days) in healthy volunteers after taking the immediate-release tablet and the two-layer modified release tablet of the present invention;

FIG. 10 is a graph showing the plasma concentration of guaifenesin after a certain time (the last 12-hour interval from the 11 twelve-hour intervals described above) in healthy volunteers after taking the immediate-release tablet and the two-layer modified release tablet of the present invention;

FIG. 11 is a graph showing an averaged plasma concentration of guaifenesin over a 16-hour period in 27 healthy volunteers: starving volunteers taking 600 mg of a two-layer modified release tablet of the present invention; starving

- 4,007156 volunteers who took 1200 mg of a two-layer modified release tablet of the present invention; and in volunteers eating very fatty foods and taking 1200 mg of a two-layer modified release tablet of the present invention;

FIG. 12 is a diagram showing a dissolution profile of dextromethorphan hydrobromide in three different doses of a 1200 mg guaifenesin-60 mg dextromethorphan tablet over a 12-hour period, measured in weight percent of dextromethorphan hydrobromide dissolved over time;

FIG. 13 is a diagram showing the plasma concentration of guaifenesin after administration of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide to volunteers both individually and in the compositions of the present invention;

FIG. 14 is a graph showing plasma concentrations of dextromethorphan hydrobromide after administering to volunteers 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide in three different compositions;

FIG. 15 is a graph showing plasma concentrations of a dextrorphan metabolite after administration of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide to volunteers in three different compositions;

FIG. 16 is a diagram showing a dissolution profile of pseudoephedrine hydrochloride in three different doses of a 1200 mg guaifenesin tablet — 120 mg of pseudoephedrine hydrochloride over a 12-hour period, measured in weight percent pseudoephedrine hydrochloride dissolved over time;

FIG. 17 is a diagram showing the plasma concentration of guaifenesin after administration of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride to volunteers separately and in the compositions described in this invention;

FIG. 18 is a diagram showing plasma concentrations of pseudoephedrine hydrochloride after administration of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in three different compositions;

FIG. 19 is a graph showing the plasma concentration of three different doses of 1200 mg of guaifenesin in Groups A, B, and C of Example 12;

FIG. 20 is a graph showing the plasma concentration of three different doses of 120 mg of pseudoephedrine in Groups A, B, and C of Example 12;

FIG. 21 is a graph showing the plasma concentration of three different doses of 1200 mg of guaifenesin in Groups A, B, and C of Example 13;

FIG. 22 is a graph showing the plasma concentration of three different doses of 120 mg of pseudoephedrine in Groups A, B, and C of Example 13;

FIG. 21 depicts guaifenesin concentrations in various compositions and dosage rates;

FIG. 22 depicts plasma concentrations of pseudoephedrine after administration of pseudoephedrine in two doses of varying intensities, as well as various compositions;

FIG. 23 depicts plasma concentrations of guaifenesin after administration of 1200 mg of guaifenesin with 120 mg of pseudoephedrine hydrochloride in two different compositions after ingestion of very fatty foods;

FIG. 24 depicts concentrations of pseudoephedrine after administration of 1200 mg of guaifenesin with 120 mg of pseudoephedrine hydrochloride in two different compositions after ingestion of very fatty foods;

FIG. 25 depicts steady-state plasma concentrations of guaifenesin after administration of 11 doses of 120 mg of pseudoephedrine with 1200 mg of guaifenesin in two different compositions;

FIG. 26 depicts steady-state plasma concentrations of pseudoephedrine after administration of 11 doses of 120 mg of pseudoephedrine with 1200 mg of guaifenesin in two different compositions;

FIG. 27 depicts plasma concentrations of guaifenesin after administration of 1200 mg of guaifenesin with and without 120 mg of pseudoephedrine;

FIG. 28 depicts plasma concentrations of pseudoephedrine after administration of 120 mg of pseudoephedrine with and without 1200 mg of guaifenesin;

FIG. 29 depicts plasma concentrations of guaifenesin after administration of a composition of 1200 mg of guaifenesin - 120 mg of pseudoephedrine to feeding and starving volunteers;

FIG. 30 depicts plasma concentrations of pseudoephedrine after administration of an experimental composition of 1200 mg of guaifenesin - 120 mg of pseudoephedrine to feeding and starving volunteers;

FIG. 31 shows dissolution profiles of guaifenesin for various doses relevant to these studies;

FIG. 32 depicts dissolution profiles of pseudoephedrine for various doses relevant to these studies;

FIG. 33 shows plasma concentrations of guaifenesin after administration of 1200 mg of guaifenesin with or without 60 mg of dextromethorphan hydrobromide;

- 5 007156 of FIG. 34 shows the average plasma concentration of dextromethorphan after administration of dextromethorphan hydrobromide in the form of various compositions, doses and dosage regimens;

FIG. 35 depicts plasma concentrations of guaifenesin after administration of 1200 mg of guaifenesin along with 60 dextromethorphan hydrobromide in three different compositions;

FIG. 36 depicts plasma concentrations of dextromethorphan after administration of 60 mg of dextromethorphan hydrobromide at three different speeds;

FIG. 37 depicts plasma concentrations of guaifenesin after administration of an experimental composition of 1200 mg of guaifenesin and 60 mg of dextromethorphan to feeding and starving volunteers;

FIG. 38 depicts plasma concentrations of dextromethorphan after administration of 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin to feeding and starving volunteers;

FIG. 39 depicts steady-state plasma concentrations of guaifenesin after repeated administration of a dose of 1200 mg of guaifenesin in various compositions;

FIG. 40 depicts mean steady state profiles of single plasma concentrations of guaifenesin;

FIG. 41 depicts steady-state plasma concentrations of dextromethorphan after repeated administration of a dose of 60 mg of dextromethorphan hydrobromide in the form of various compositions and / or different dosage rates;

FIG. 42 depicts plasma concentrations of dextromethorphan after administration of 60 mg of dextromethorphan hydrobromide in the form of various compositions and / or different dosage rates;

FIG. 43 is a flowchart of a manufacturing process of a 95% guaifenesin concentrate;

FIG. 44 is a flow chart of the manufacture of guaifenesin / pseudoephedrine tablets (1200/120 mg);

FIG. 45 is a flow chart of the manufacture of guaifenesin / pseudoephedrine tablets (600/60 mg).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to delayed release formulations of guaifenesin. In a preferred embodiment, the compositions also include at least one additional drug in an immediate release form, a slow release form, or both. Each composition includes a certain amount of guaifenesin and may optionally contain at least one additional drug. The immediate release composition is formulated to dissolve in an acidic aqueous medium such as gastric juice to provide rapid release of guaifenesin, and optionally at least one additional drug. In a preferred embodiment, the slow-release composition comprises a combination of a hydrophilic polymer and a water-insoluble polymer in the range of about 1: 1 (one to one) to 9: 1 (nine to one), more preferably in the range of about 3: 2 (three to two) - 6: 1 (six to one) and most preferably in the range of a ratio of approximately 2: 1 (two to one) - 4: 1 (four to one).

In a preferred embodiment, the hydrophilic polymers are selected from gum arabic, tragacanth gum, carob gum, guar gum, or caramel gum, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, agarine, carboxyene, pectin, gelatin, pectin, carboxymethyl gelatin, pectin 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 of the type Metocel | Mc11uyes1 (E10M)]. Preferred total amounts of a hydrophilic polymer for a 1200 mg tablet include more than 0.5 and less than 10% by weight. More preferably, the amounts of hydrophilic polymer include more than 1.0 and less than 7.0%, more than 2 and less than 6.0%. These amounts include a hydrophilic polymer in the composition of the guaifenesin concentrate described below. The hydrophilic polymer, which is added separately to form a slow release matrix, is from about 0.5 to 4.0%, and more preferably from about 1.0 to 2.0%. It should be borne in mind that these amounts may be proportionally present in a 600 mg tablet or in a composition of any desired strength.

In a preferred embodiment, water-insoluble polymers are selected from polyacrylic acids, acrylic resins, acrylic latex dispersion, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxymethylpropyl cellulose phthalate. In a more preferred embodiment, water-insoluble polymers are selected from acrylic resins. In a most preferred embodiment, the water-insoluble polymers are selected from carbomer acrylic resins (Cacterium aeguide gecko) of the Cacterium 934P type. Preferred amounts of water insoluble polymer include more than about 0.5% and less than about 2.5% by weight for a 1200 mg tablet. More preferably, the amounts of hydrophilic polymer include more than about 15 and less than about 1.5% and most preferably more than about 0.9 and less than

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1.25%. It should be borne in mind that these amounts may be proportionally present in a 600 mg tablet or in any composition of desired strength.

The invention also relates to delayed release compositions of the type described above in the form of bilayer tablets or capsules having a combination of beads or granules with an immediate release composition or beads or granules with a delayed release composition. Alternatively, the slow release composition may include a core that is coated with a layer of the immediate release composition and thus form a separate tablet. For the purpose of illustration, the invention will be described in detail in the context of a bilayer tablet. If the object of the implementation is a two-layer tablet, then such a tablet is prepared in two parts: one part includes a slow-release composition, and the second part - an immediate-release composition. In a preferred embodiment, at least one additional drug may be present in the slow release composition or the immediate release composition, or both, depending on the desired effect.

For example, a preferred embodiment of the present invention in a layer of a slow release composition contains the following components and has the following dimensions (mg / tablet):

1052.6 mg of 95% guaifenesin concentrate [Oiayepez ES (95%)] [1000.0 mg guaifenesin, CBR and

52.6 mg hydroxypropyl methylcellulose, CBR]; 120.0 mg pseudoephedrine hydrochloride, CBR; 30.0 mg hydroxypropylmethyl cellulose, CBR [Me11use1 E10M, CBR]; 15.0 mg carbomer 934P (Cacterothera 934P), ΝΡ [Cactoro 974P]; 0.4 mg of dye ΡΌ & Ο Keb # 40 A1ittit Bake (14-16%) and 10.0 mg of magnesium stearate, ΝΡ for the total amount of delayed-release composition by 1228.0 mg. In a preferred embodiment, the immediate-release layer has the following composition: 210.5 mg of guaifenesin 95% concentrate [Oiayepez ES (95%)] [200.0 mg of guaifenesin, CBR and 10.5 mg of hydroxypropyl methylcellulose, CBR]; 117.5 mg microcrystalline cellulose, ΝΡ [Ανίοεί ΡΗΙ02]; 30.0 mg sodium starch glycolate, ΝΡ [EXBOTAB] and 1.0 mg magnesium stearate, ΝΡ for the total immediate release composition of 359.0 mg.

In another preferred embodiment, a 1200 mg guaifenesin / 120 mg pseudoephedrine tablet has the following components and ratios:

Component number (mg / tablet) Representative batch (kg) ¹ HB layer Representative batch (kg) ¹ SW layer Guaifenesin OS (95%) ² 1263.1 280.00 947,376 Hydroxypropyl methyl cellulose 30,0 Ν / Α 27,000 a (MeYlose1 ™) Pseudoephedrine hydrochloride 120.0 Ν / Α 108,0 Cellulose 117.50 156.28 Ν / Α microcrystalline Sodium Glycolate Starch 30,0 39.90 Ν / Α Carbomer 934Р 15.0 Ν / Α 13,500 Magnesium stearate 11.0 1.33 9,000 RO & S Keb # 40 Akipshish Bake 0.4 Ν / Α 0.360 (14-16%) Purified water Ν / Α ³ Ν / Α ³ Ν / Α ³ Total weight 1587.0 477.51 1105,236

¹ Based on a batch size of 900,000 tablets.

² The composition used in the production of guaifenesin by pressing consists of 95% guaifenesin, CBR, 5% hydroxypropyl methylcellulose, CBR (Me11use1 ™ E10M), granulated together with purified water, CBR (49.21 kg).

³ When processing guaifenesin ES (95%), water is removed.

In another preferred embodiment, a 600 mg guaifenesin / 60 mg pseudoephedrine tablet has the following components and ratios:

Component number (mg / tablet) Representative batch (kg) ¹ HB layer Representative batch (kg) ¹ SW layer Guaifenesin ΏΟ (95%) ² 631.55 280.00 947,376 Hydroxypropyl methyl cellulose 15.0 Ν / Α 27,000 (MeJuice! ™) Pseudoephedrine hydrochloride 60.0 Ν / Α 108,0 Microcrystalline cellulose 58.75 156.28 Ν / Α Sodium Glycolate Starch 15.0 39.90 Ν / Α Carbomer 934Р 7.5 Ν / Α 13,500 Magnesium stearate 5.50 1.33 9,000 RC & S Kes1 # 40 A1itpsht bake 0.8 Ν / Α 1,440 (14-16%) Purified water Ν / Α ³ Ν / Α ³ Ν / Α ³ Total weight 794.1 477.51 1106,316

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

² The composition used in the production of guaifenesin by pressing consists of 95% guaifenesin, CBR, 5% hydroxypropyl methylcellulose, CBR (Me11use1 ™ E10M), granulated together with purified water, CBR (49.21 kg).

³ When processing guaifenesin ES (95%), water is removed.

In another example, a 1200 mg tablet of guaifenesin / 120 mg of pseudoephedrine may have the following properties:

Description 1200 mg two-layer tablet Average tablet weight 1587.0 mg ± 3% (1539.4 mg - 1634.6 mg) Tablet thickness 0.32 G’-0.341 ” Tablet hardness 25-45 8C Fragility No more than 0.8% Loss on drying (humidity) No more than 2.0% Not more than 31.74 mg / dose unit Guaifenesin Analysis 1140.0 - 1260.0 mg / tablet (95.0 - 105.0%) Pseudoephedrine Hydrochloride Analysis 116.6 - 128.4 mg / tablet (93.0 - 107.0%) Guaifenesin Identification A The delay time of the peak obtained as a result of the analysis corresponds to the parameter of the Standard drug Guaifenesin (Identification B) Intensively formed cherry red to purple color. Delay time of the peak resulting from

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Pseudoephedrine hydrochloride Identification A analysis, corresponds to the standard preparation parameter Pseudoephedrine hydrochloride Identification B The IR spectrum corresponds to the spectrum of the standard in the region of 2510 cm ⁴ - 2400 cm ⁴ Dose uniformity % Κ8ϋ not more than 6.0% (% Κ.8ϋ not more than 7.8% for Level II) All individual values between 85.0 -115.0% (For Tier II, one value is outside 85.0 - 115.0%, but not outside 75.0 - 125.0%) Dissolution 1 Hour: not more than 45% Guaifenesin 2 Hours: 36-56% 6 Hours: 61 - 81% 12 Hours: at least 85% Dissolution Pseudoephedrine hydrochloride 1 Hour: MORE THAN 53% 2 Hours: 48-68% 6 Hours: at least 81% 12 Hours: at least 85%

In another example, a 600 mg guaifenesin / 60 mg pseudoephedrine tablet may have the following properties:

Description Average tablet weight Tablet thickness Tablet hardness Fragility 600 mg two-layer tablet 794.1 mg ± 3% (766.4 mg - 821.8 mg) 0.247 ”-0.262” 17-32 psi No more than 0.8% Loss on drying (humidity) No more than 2.0% No more than 15.88 mg / unit dose Guaifenesin Analysis 570.0 - 630.0 mg / tablet (95.0 - 105.0%) Pseudoephedrine Hydrochloride Analysis 58.2 - 61.8 mg / tablet (93.0 - 107.0%) Guaifenesin Identification A The delay time of the peak obtained as a result of the analysis corresponds to the parameter of the Standard drug

-9007156

Guaifenesin (Identification B) Intensively formed cherry red to purple color. Pseudoephedrine hydrochloride Identification A The delay time of the peak obtained as a result of the analysis corresponds to the parameter of the Standard drug Pseudoephedrine hydrochloride Identification B The IR spectrum corresponds to the spectrum of the standard in the region of 2510 cm ⁴ - 2400 cm ⁴ Dose uniformity % no more than 6.0% (% K.8E no more than 7.8% for Level II) All individual values between 85.0 - 115.0% (For Tier II, one value is outside 85.0 115.0%, but not outside 75.0 -125.0%) Dissolution 1 Hour: not more than 48% Guaifenesin 2 Hours: 41-61% 6 Hours: 73-93% 12 Hours: at least 90% Dissolution Pseudoephedrine hydrochloride 1 Hour: not more than 58% 2 Hours: 56-76% 6 Hours: at least 80% 12 Hours: at least 85%

In one embodiment, the weight specification of 1200/60 mg of guaifenesin / dextromethorphan is 1530.4 mg ± 3.0% and corresponds to a range of 1484.5 - 1576.3 mg. For a 600/30 mg tablet, the weight specification is 765.2 mg ± 3.0% and corresponds to the range of 742.2 - 788.2 mg. This specification range of ± 3.0% of theoretical weight is similar to one tablet of guaifenesin, 600 mg and 1200 mg, respectively.

The proposed hardness and thickness specifications for 1200/60 mg tablets of guaifenesin / dextromethorphan are 15-65 8Ci and 0.310-0.340, respectively. Tablets pressed at 527 tablets per minute, with a minimum hardness parameter (12BB86A), ranged from 0.329 - 0.334 and 17-23 8Ci. Fragility varied between 0.20-0.33%. Tablets, pressed at 737 tablets per minute, with a minimum hardness parameter (12BB86B) ranged from 0.331 - 0.335 and 15-24 8Ci. The fragility was 0.20-0.39%. A solubility test was performed for each test condition (527 tablets per minute and 737 tablets per minute) for one hour after compression. There were no significant differences in the release profile between test samples and experimental batches.

Subsequently, tablets pressed in the form of the thinnest and hardest products, as far as the press allowed at speeds of 527 tablets per minute (12BB86C) and 737 tablets per minute (12BB86O), had a thickness in the range of 0.303 - 0.312 with a corresponding initial hardness range of 39-47 8Ci at 527 tablets per minute. The fragility varied in the range of 0.07-0.13%. A thickness range of 0.304-0.313 was obtained with a corresponding initial hardness range of 38-47 8Ci at 737 tablets per minute. The fragility was in the range of 0.06-0.13%. Over time, it was noted that during the first few days after pressing, these tablets become harder. Therefore, at least 5 days after compression, these “hard” tablets were tested for solubility. The hardness range on the fifth day after pressing was 52-60 8Ci for tablets pressed at 527 tablets per minute. The hardness range on the fifth day after pressing was 48-56 8Ci for tablets pressed at 737 tablets per minute. The solubility profile for test samples in this case also closely coincided with the corresponding indices of the experimental batches. In addition, for PB01-H30, by the end of the 3-month stability interval in real time, the tablet hardness range was 60-79 8C11. There were no significant differences from T _o in the dissolution profile.

The proposed hardness and thickness specifications for 600/30 mg tablets of guaifenesin / dextromethorphan were 15-65 8Ci and 0.220 - 0.260, respectively. Tablets pressed with a minimum hardness parameter at 527 tablets per minute (12BV85A) ranged between 0.257 - 0.260 and 8-13 8Ci. Fragility varied within 0.13-0.26%. Tablets pressed with a minimum hardness parameter at 840 tablets per minute (12B85B) ranged between 0.258 - 0.261 and 8-13 8Ci. The fragility was 0.13-0.26%. A solubility test was performed for each condition tested (527 tablets per minute and 840 tablets per minute) for one

- 10007156 hours after pressing. There were no significant differences in the release profile between test samples and experimental batches.

After this, the tablets were pressed in the form of the most thin and solid products, as far as the press allowed. When pressed at 527 tablets per minute (12B85C), a range of 0.232-0.241 and a corresponding hardness in the range of 25-30 8CI were obtained. The fragility was 0.13-0.78%. On the seventh day after pressing, the hardness was 28-34 8 SI. When pressed at 840 tablets per minute (12ΕΒ85Ό), a range of 0.230 - 0.241 was obtained and the corresponding hardness was in the range of 23-30 8SI. The fragility was 0.00-0.13%. On the seventh day after pressing, the hardness varied within 2833 8 SI. The solubility profile for the tested samples in this case also closely coincided with the corresponding indices of the experimental batches. In addition, for PB01-H54, by the end of the 3-month stability interval in real time, the tablet hardness range was 3751 8 SI. There were no significant differences from T ₀ in the dissolution profile.

Preferred tablets are 1200 mg of guaifenesin / 60 mg of dextromethorphan have an average thickness of 0.305-0.335, an average tablet hardness of 25-35 8 SI (during operation), and an average tablet hardness (during release) of 20-79 8 SI on average.

Preferred tablets are 600 mg of guaifenesin / 30 mg of dextromethorphan have an average thickness of 0.230-0.260, an average hardness of a tablet of 20-30 8 SI (during operation), and an average hardness of a tablet (during release, over its expiration date) is on average 10-51 8 SI .

A specification of not more than 0.8%, given as an indicator of the fragility of both guaifenesin / dextromethorphan tablets, is based on the limit set with tablets containing only guaifenesin. The specification indicating loss on drying is comparable to tablets containing only guaifenesin and having this specification, not more than 2.0%. The moisture limit is 2.0% of the total theoretical weight of the tablet, registered as mg / unit dose.

The specification range for guaifenesin is based on a specific quantity, 1200 mg or 600 mg ± 4.0%. For a 1200/60 mg tablet of guaifenesin / dextromethorphan, the range is 1152.01248.0 mg per tablet. For a 600/30 mg tablet of guaifenesin / dextromethorphan, the range is 576.0-624.0 mg per tablet. The specification range for dextromethorphan hydrobromide is based on a specific amount of 60 mg or 30 mg ± 4.0%. For a 1200/60 mg tablet, the range is 57.662.4 mg per tablet. For a 600/30 mg tablet, the range is 28.8-31.2 mg per tablet.

Other embodiments of the present invention include 8SI, which is preferably less than 43, more preferably less than 41, more preferably less than 38, more preferably less than 37 and more preferably is between 32 and 35. 8SI is also preferably more than 21, more preferably more than 24, more preferably more than 28, and more preferably more than 31.

The weight of 10 bilayer tablets of guaifenesin / pseudoephedrine (1200 mg / 120 mg) is preferably less than 16.4 g, more preferably less than 16.35 g, more preferably less than 16.29 g, more preferably less than 16.22 g, more preferably less than 16.16 g, more preferably less than 16.10 g, more preferably less than 16.04 g and more preferably between 15.71 g and 16.03 g. The weight of 10 two-layer tablets is also preferably more than 15, 35 g, more preferably more than 15.40 g, more preferably more than 15.46 g, more prev significantly more than 15.53 g, more preferably more than 15.59 g, more preferably more than 15.65 g.

Other implementations and features of the present invention are described in detail below.

Slow Release Composition

In one embodiment of the invention, the delayed release composition comprises guaifenesin and optionally at least one drug, which are mixed with a polymer blend comprising at least one hydrophilic polymer and at least one water insoluble polymer. In another embodiment, the delayed release composition may include a combination of guaifenesin and at least one additional drug, where the additional drug may be selected, among others, from a cough agent such as dextromethorphan hydrobromide, codeine, dihydroxycodeinone, decongestant such as phenylephrine hydrochloride, hydrochloride phenylpropanolamine, pseudoephedrine hydrochloride, or ephedrine, an antihistamine such as chlorpheniramine maleate, maleate and brompheniramine, phenindiamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, and clemastine fumarate, an analgesic such as aspirin, ibuprofen, naprosin and acetaminophen, or combinations thereof. Preferably, the medicament is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.

As described below, in order to achieve the desired профиляη νίνο release profile, polymers are used in the slow release matrices. To achieve the desired release profile, proper mixing is necessary, as well as the selection of an appropriate formulation. For example, too high a hydrophilic polymer content leads to too rapid release, and not

- 11 007156 provides a 12-hour therapeutic effect, while too high a hydrophobic polymer content, in terms of symptom relief, leads to inadequate C _max . Therefore, the choice of polymers, their total amount used, their mutual ratio allows you to prepare a matrix that is formulated according to the methods below and provides an appropriate release profile.

Hydrophilic polymers suitable for use in delayed release compositions include one or more natural or partially or fully synthetic, hydrophilic resins such as gum arabic, tragacanth gum, carob, guar gum or caravan gum, modified cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose; carboxymethyl cellulose; protein substances such as agar, pectin, carrageenan and alginates; as well as other hydrophilic polymers such as carboxypolymethylene, gelatin, casein, zein, bentonite, aluminum silicate, polysaccharides, modified starch derivatives and other hydrophilic polymers known to those skilled in the art, or a combination of such polymers.

It is this hydrophilic polymer gel that dissolves slowly in acidic aqueous media, thus allowing guaifenesin and at least one drug to diffuse from the gel into the stomach. When the gel reaches the intestines, where guaifenesin and the drug can be rapidly absorbed, the gel is dissolved in controlled amounts in a high pH medium and provides a slow release of guaifenesin and at least one drug throughout the digestive tract. Preferred hydrophilic polymers are hydroxypropylmethyl celluloses, such as those manufactured by Eo \\ Cbeta1 and known as metocell ethers (Me11cu1e1ke5). In one preferred embodiment of the slow release composition, the hydrophilic polymer is a metocell ester known as Me11use1 E10M.

Water-insoluble polymers that are suitable for use in sustained release formulations are polymers that generally do not dissolve in solvents below pH 5 and more slowly dissolve in alkaline solutions than the hydrophilic polymer. Since the polymer is not soluble in low pH environments such as gastric juice, this slows down the release of the drug in the surrounding areas. Since the polymer dissolves in solutions with high pH more slowly than hydrophilic polymers, this helps to slow down the release of the drug throughout the intestine. Such a significant delay in release leads to a more uniform plasma concentration of guaifenesin.

Water-insoluble polymers suitable for use in this invention include, for example, polyacrylic acids, acrylic resins, acrylic latex dispersion, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxymethyl propyl cellulose phthalate and other polymers known to those skilled in the art. In a preferred embodiment, the slow release composition comprises a Cazoro 974P acrylic resin provided with BE CoPSN.

The delayed release composition of the present invention may further contain, among others, the following pharmaceutical additives: lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, and mineral oil; dyes; binders such as sucrose, lactose, gelatin, starch paste, gum arabic, tragacanth, polyethylene glycol povidone, Pullulan and corn syrup; polishing agents such as colloidal silicon dioxide and talc; surface active agents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxacol, and quaternary ammonium salts; preservatives and stabilizers; fillers such as lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, chloride, sulfates and phosphates of potassium, sodium, and magnesium; and / or any other pharmaceutical additives known to those skilled in the art. Dyes, along with others, include: EtegaN Szheep Bake, EE & S Web Yo. 40, EE & C Ye11o \ g Yo. 6, E & C Ye11o \ g Yo. 10, EE & C B1ie Wo. 1 and other various certified color additives (see 21 SEV, part 74). In one preferred embodiment, the slow release composition further comprises magnesium stearate and the dye Etega1b Sgiep Bake. In another preferred embodiment, the slow release composition further comprises magnesium stearate and dye EE & C B1ie N0. 1 L1ish1pit bake Tsue.

In another embodiment, the modified release composition 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 that dissolves the drugs in a therapeutically effective profile for a longer period of time. Preferably, the medicament provides a therapeutically effective profile for more than 10 hours, more preferably more than 12 hours and most preferably more than 14 hours. In a preferred embodiment, the modified release composition comprises about 75-95% by weight of guaifenesin, about 1-15 wt.% add

- 12 007156 medicinal product, approximately 0.5-10% hydroxypropyl methylcellulose, approximately 0.5-2.5% acrylic resin, approximately 0.4-1.5% magnesium stearate and approximately 0.01-1% by weight of the dye . In a more preferred embodiment, the modified release composition comprises about 75-80% by weight of guaifenesin, about 3-10% by weight of the additional drug, about 3-6% hydroxypropyl methylcellulose, about 1-1.5% acrylic resin, about 0.7- 1% magnesium stearate and approximately 0.03-0.13 wt.% Dye.

The delayed-release composition controls the release of guaifenesin and optionally at least one additional preparation in the digestive tract over a longer period of time and provides an improved profile compared to immediately-releasing compositions. The solubility of guaifenesin is affected by the pH of the environment (in this case, the stomach and intestines). In a more acidic environment, such as a stomach, guaifenesin is less soluble, while in an environment with a higher pH, such as an intestine, guaifenesin is readily soluble. Changes in pH throughout the digestive tract affect the solubility rate of guaifenesin and partially determine the concentration of guaifenesin in the blood and tissues.

In order to maintain a plasma concentration of guaifenesin providing a good therapeutic effect, the release or dissolution of guaifenesin from the matrix of the composition throughout the intestine should be delayed and / or controlled. Hydrophilic and water-insoluble delayed-release gel polymers are exposed to low pH environments. In a medium with a higher pH, this gel matrix allows delayed-release drugs, for example, one guaifenesin or its combination with a second drug, to diffuse at a controlled rate.

When using drugs approved by the Health Administration (Eob apb Egid ΛάιηίπίδΙηΙίοη (ΡΌΆ)) for the quality of food and medicine, a slow-release composition can be formulated so that it mimics the plasma profile of guaifenesin and any additional drug (s) like it is described in clinical documents according to the requirements of ΡΌΆ, or as required by ΡΌΆ. In other words, the slow release composition releases at least one additional drug at the same rate as the commercially available composition, thus providing a therapeutically effective amount of the additional drug.

In a preferred embodiment, the slow release composition comprises a hydrophilic polymer and a water insoluble polymer in a ratio of about 1: 1 (one to one) to 9: 1 (nine to one), more preferably in a ratio of about 3: 2 (three to two) - 6: 1 (six to one) and most preferably in a ratio of approximately 2: 1 (two to one) to 4: 1 (four to one). In another embodiment, the slow release composition comprises not more than about 10% hydrophilic polymer, preferably not more than 6%; in a more preferred embodiment, the slow release composition also comprises no more than 2.5 wt.% of a water insoluble polymer. In another preferred embodiment, the hydrophilic in water polymer is hydroxypropyl methyl cellulose, and not the water soluble polymer is acrylic resin. These ratios provide a plasma concentration profile of guaifenesin that provides an optimal therapeutic concentration for approximately 12 hours.

Slow-release composition can be prepared according to any appropriate method known to specialists in pharmaceutical production. In one embodiment, guaifenesin and a hydrophilic polymer may be mixed in an mixer with an aliquot of water to form wet granules. The granules can be dried to obtain guaifenesin granules encapsulated in a hydrophilic polymer. The resulting granules can be crushed, sorted and then mixed with various pharmaceutical additives, with a water-insoluble polymer and an additional hydrophilic polymer. After that, the composition can be molded in the form of tablets, and the tablets are further coated with a protective film that quickly dissolves or disperses in the gastric juice.

In a preferred embodiment, a method for preparing a slow release composition comprises loading about 126 kg of guaifenesin and about 2 kg of E10M metocel into a high knife mixer. Metocel E10M and guaifenesin can be mixed for approximately 7 minutes at a mixing speed of approximately 150 rpm and a crumbling rate of approximately 2000 rpm. After this, the mixing and crumbling speeds can be increased to approximately 200 and 3000 rpm./min, respectively, for approximately 5 minutes, while approximately 49 kg of water are added to the mixer contents. The mixer can work for two additional minutes to complete the granulation. In another preferred embodiment, the switch for the mixer load is set to 21 kV.

Wet granules can be discharged into a fluidized bed tank and placed in a fluidized bed dryer mounted on the dryer air stream at 900 cubic feet (25.48 m ³ ) per minute and outlet temperature of about 50-55 ° C, while the temperature the output will not increase at a rate of 1 ° C per minute. After that, the air stream may

- 13 007156 be reduced to 600 cubic feet (16.99 m ³ ) per minute and the inlet temperature can be reduced to 43 ° C until the granules are dried to a moisture content of not more than 0.5%. In another preferred embodiment, the outlet temperature is set to off at 48 ° C. In yet another preferred embodiment, the agitator in the fluidized bed reservoir can be operated periodically during drying. The dried granules can be passed through a mill equipped with a sieve of the appropriate size so that no more than approximately 30% of the finished granules pass through a 100 mesh sieve, and no more than approximately 10% of the obtained granules are retained by a 10 mesh sieve. In one preferred embodiment, the dried granules can be passed through a mill equipped with a 0.109 sieve at a mill speed of about 500-1500 rpm and a screw feed speed of about 35-45 rpm. The resulting sorted granules contain approximately 95% guaifenesin and will hereinafter be referred to as directly compressed guaifenesin [6 Oiabepect ES (Όίτβεΐ Sotrgeckeb)]. The sorted granules can then be transferred to a V mixer, with a volume of 10 cubic feet (0.28 m ³ ), where they are combined with approximately 0.6 kg of E10M metocel, approximately 0.3 kg of dye type EtegaBbeep Bake or EE & C Bie E. 1, approximately 0.7 kg of magnesium stearate and approximately 1.3 kg of 974P carbopol. The combination may be mixed for approximately 3 minutes.

In another preferred embodiment, a method for preparing a slow release composition comprises loading about 101-150 kg guaifenesin, about 4.5-18 kg additional drug, about 4.5-5 kg metocel E10M, about 1.52.25 kg carbopol ® 974P and approximately 40-240 g of dye in a high knife mixer. If water needs to be added by this time, then approximately 1-1.5 kg of magnesium stearate is also added with it. The components can be mixed for about 10-12 minutes at a mixing speed of about 150 rpm and a crumbling speed of about 2000 rpm. After this, the mixing and crumbling rates can be increased to approximately 200 and 3000 rpm, respectively, for approximately 5 minutes, while approximately 29 kg of water are arbitrarily added to the contents of the mixer. If no water is added, then approximately 1-1.5 kg of magnesium stearate can be added to the contents of the mixer during this time. To complete the granulation, the mixer can work for an additional 10 minutes. In another preferred embodiment, the switch for the mixer load is set to 21 kV.

Wet granules can be discharged into a fluidized bed tank and placed in a fluidized bed dryer mounted on the dryer air stream at 900 (25.48 m ³ ) cubic feet per minute and an outlet temperature of approximately 38-48 ° C, while the output will not increase at a rate of 1 ° C per minute. After that, the ventilation stream can be reduced to 600 (16.99 m ³ ) cubic feet per minute, and the inlet temperature can be reduced to 43 ° C until the granules are dried to a moisture content of not more than 0.5%. In another preferred embodiment, the outlet temperature is set to off at 48 ° C. In yet another preferred embodiment, the agitator in the fluidized bed reservoir can be operated periodically during drying. The dried granules can be passed through a mill equipped with a sieve of the appropriate size, so that no more than approximately 30% of the finished granules pass through a 100 mesh sieve and no more than approximately 10% of the obtained granules are retained by a 10 mesh sieve. In one preferred embodiment, the dried granules can be passed through a mill equipped with a sieve of about 0.109-0.125 (0.28-0.32 cm) in size, with a mill speed of about 500-1500 rpm and a screw feed speed of about 35-45 rpm. / min

Further, the resulting compositions can be pressed onto a tablet machine using an appropriate set of tablet forming tools.

The tablets may be of any appropriate weight, size and shape, depending on the desired dosage strength of the tablets. In one embodiment, these tablets can then be loaded into the coating bath, coated with a protective film of opadri U-8-3-714 (Orabgu Υ-8-3-714) (provided with Co1ogsop, 1 ps) and air-dried.

In another embodiment, a method for preparing a sustained release composition comprises mixing drugs, a hydrophilic polymer, a water insoluble polymer, and any pharmaceutical additives. After that, the resulting mixture can be pressed into tablets and, if desired, coated with a protective layer that quickly dissolves or disperses in the gastric juice. In a preferred embodiment, approximately 126 kg of guaifenesin OC (approximately 95% purity), approximately 2.6 kg of metocel E10M, approximately 1.3 kg of carbopol 974P and approximately 0.333 kg of colorant type Etega bbeep bake or EE & C bie No.. 1 can be loaded into a 10 cubic foot V mixer. The components can be mixed for approximately 20 minutes, during which time approximately 0.6 kg of magnesium stearate can be added to the mixed components. This mixture can be mixed for an additional 10 minutes. Further, the resulting composition can be pressed onto a tablet machine using an appropriate set of tablet forming tools. The tablets may be of any appropriate weight, size and shape, depending on the desired dosage strength of the tablets. These tablets may further be heavy.

- 14 007156 into the bath for coating, covered with a protective film of opadri Υ-8-3-714 (supplied with С1огсоп, 1 ps) and dried in the bath with air.

One embodiment of the present invention uses the following general manufacturing methods. To prepare guaifenesin OS (95%), intermediate granulation is performed. Purified water И8Р is loaded into the granulator. Next, guaifenesin I8P is introduced into the granulator. Then, I8P hydroxypropyl methylcellulose (E1-OM metocel) is added. Intermediate guaifenesin is air dried, setting the inlet temperature to about 5 ° C until the outlet temperature reaches about 48 ° C. After that, a sample can be taken for intermediate testing (determination of humidity). After the material reaches the target moisture level, the mixture is unloaded and prepared for grinding. After that, the dried granules are transferred to a grinding machine and the grinding process is started. Again, a sample can be taken for intermediate testing (to determine moisture and analyze particle size distribution). The ground material is collected in double-edged calibrated cardboard drums from polyethylene packets containing bags with a moisture absorber between the inner and outer plastic bags and sent for homogenization. Lots of product are homogenized in a 60 cubic foot mixer for at least 10 minutes. Again, a sample can be taken for intermediate testing (description, humidity, homogenized sample test and particle size analysis). The final analysis of the particle size distribution of ground guaifenesin OS will preferably be as follows: no more than about 2-10%, held by a sieve with 10 mesh (2.00 mm), no less than about 50-60%, held by a sieve with 20-100 mesh (150 cm ), not less than approximately 4-6% passing through a sieve with 100 mesh and not more than approximately 15-20% passing through a sieve with 140 mesh (106 cm). If at least 50% and preferably at least 60% of guaifenesin OS has a particle size in the range of about 2 mm - 150 cm, this facilitates the processing and achievement of the desired release profile ίη νΐνο for both a single-component drug and a combined drug composition described above. Finally, OS guaifenesin granules (95%) are collected in tared cardboard drums, with double edging from two-layer polyethylene bags, containing bags with a moisture absorber between the inner and outer plastic bags.

In one embodiment, an immediate release layer is prepared according to the following general procedures. The obtained components, guaifenesin OS (95%) and microcrystalline cellulose, ΝΕ (Αν№1 ® PH102), are weighed and homogenized in a RK U-mixer (Patrick Kelly U-mixer) for approximately 20 minutes. Thereafter, sodium starch glycolate, Е (Exp1o! Ab®), is added to the mixture, and the mixture is stirred for approximately 10 minutes. Next, magnesium stearate, ΝΕ, is added to the homogenate, and the mixture is mixed for approximately an additional 10 minutes. After this, a sample can be taken for intermediate testing (description, testing of a homogenized sample and analysis of particle size distribution).

In one embodiment, a slow release layer is prepared according to the following general procedures. The obtained components, guaifenesin OS (95%) and pseudoephedrine hydrochloride, И8Р, previously passed through a No. 20 sieve, are weighed and mixed for 10 minutes with hydroxypropylmethylcellulose, И8Р (metocel E10M), carbomer 934Р and the corresponding dye (ΕΌ & С Web No.. 40 a1shit 1ake, for staining tablets 1200 mg guaifenesin / 120 mg pseudoephedrine hydrochloride or ΕΌ & С Се11ο \ ν No. 6 a1ittit 1ake, for staining tablets 600 mg guaifenesin / 60 mg pseudoephedrine hydrochloride). Then add an additional amount of guaifenesin OS (95%), previously passed through a No. 10 sieve, and homogenized for approximately 10 minutes. Then magnesium stearate, ΝΕ, previously passed through a No. 20 sieve, is added and homogenized for approximately 10 minutes. Samples can be taken for intermediate testing (description, analysis of particle size distribution and testing of homogenized samples for both guaifenesin and pseudoephedrine hydrochloride). Tablet compression involves loading each mixture (1B and 8B) into an appropriate hopper on a bilayer tablet press and then compressing the tablets according to the described parameters.

In another embodiment, tablets of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide are prepared using the following protocol. The output of the production process is 600,000 tablets per lot for tablets of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide or 1,200,000 tablets per lot for tablets of 600 mg of guaifenesin and 30 mg of dextromethorphan hydrobromide. The components for the immediate release layer (1B layer) are identical for tablets of one or the other force. The components for the sustained release layer (8B) are also identical for both tablets.

For a slow-release layer (8B layer) (for a tablet of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide), guaifenesin and dextromethorphan hydrobromide (previously passed through a 20 mesh sieve) are granulated together with carbomer 934P, hydroxypropylmethylcellulose (Metocell E # 1  dye 
 , A1ttit 1ake (11-13%) using purified water in water

- 15 007156 as liquid for granulation in a Day mixer (Bau Sh1heg). The wet mass is evenly distributed on paper trays and dried in a drying oven at 109 ± 10 ° G for approximately 25 hours, until the average moisture content of the product is not more than 1.5%. The process for the 8P layer for a 600 mg guaifenesin tablet and 30 mg dextromethorphan hydrobromide is identical to the process for a 1200 mg guaifenesin slow release tablet and 60 mg dextromethorphan hydrobromide, except for the dye used. The dye used in the half-strength tablet is B & C уе11о \ у # 10, а1иш1пит 1аке (14-18%), while the dye used in the tablet of full strength is GB & С В1е # 1, а1ит1пит 1аке (11-13% ) The dried granules are crushed using a Fitzpatrick mill (GyhraYsk) having a sieve with round holes of 0.125 (0.317 cm) and front knives at fast speed. Granules are fed to the mill using an automatic feed mechanism. After that, six auxiliary batches (each auxiliary batch of 112.04 kg, granular, dried and ground, as described above) are mixed together with magnesium stearate in a mixer with a capacity of 60 cubic feet (1,699 m ³ ) for 10 minutes.

For the ΙΡ layer, guaifenesin and dextromethorphan hydrobromide (previously passed through a 20 mesh sieve) are granulated together with sodium starch glycolate (Exp1o! Ab), microcrystalline cellulose (Avicel ΡΗΙ02) and hydroxypropylmethyl cellulose (Metocel water, 10 ml) granulation liquids in a Day mixer. The wet mass is evenly distributed on paper trays and dried in a drying oven at 109 ± 10 ° G for approximately 26 hours, until the average moisture content of the product is not more than 2.0%. The process is the same for the 8P layer for tablets of both one and the other strength. The dried granules are passed through Sveko (8 ^ ECO), which is equipped with a 10 mesh sieve. The granules remaining on a sieve with 10 mesh, crushed using a Fitzpatrick mill (P | 1hra1g1sk). having a sieve with round holes with 0.125 (0.317cm), and front knives at medium speed. Granules are fed to the mill using an automatic feed mechanism. After that, the crushed material is passed through a 10 mesh sieve. Three auxiliary batches (each auxiliary batch of 95.52 kg, granular, dried and ground, as described above) are mixed together with magnesium stearate in a 60 cubic foot (1,699 m ³ ) mixer for 10 minutes. Next, each mixture is loaded into the appropriate hopper and pressed in the form of two-layer tablets.

Tablets containing the slow release composition were prepared and tested against the release parameters ίη νίΐτο and ίη νΐνο as described below in Examples 1, 2, and 3. In the Приη νίΐτο tests, the dissolution rates of these tablets were compared with the dissolution rates of the modified delayed release tablets, formulated without an acrylic resin (Example 1), and three commercially available tablets, one of which was an immediate release composition and the other two were modified release compositions. Tablets containing the slow release composition showed a slower, more controlled release of guaifenesin over a period of 12 hours than any of the other tablets (see, for example, examples 1 and 2, and FIGS. 4 and 5).

In the ίη νΐνο test, plasma concentrations in subjects taking tablets containing the slow release composition were compared with plasma concentrations in subjects taking tablets with the immediate-release guaifenesin composition and modified guaifenesin releasing tablets formulated without acrylic resin (see Example 3 and FIG. . 6). Tablets comprising a slow release composition showed improved sustained release and better therapeutic concentration over a longer period of time compared to the other two compositions. In addition, subjects taking tablets with a slow-release composition required more time for guaifenesin to appear in the blood stream, and the maximum plasma concentration (C _max ) of guaifenesin was less than half of those taking tablets with an immediate-release composition.

Modified Release Composition

In order to improve the C _max and the rate of guaifenesin onset in patients while maintaining the therapeutic effect for approximately 12 hours, a portion of the delayed release composition as described above can be combined with a portion of the immediate release composition as a modified release product. In a preferred embodiment, at least one additional drug may be present in the slow release composition, the immediate release composition, or both, depending on the desired effect. When using drugs approved by the Food and Drug Administration (GBL), a slow-release composition, an immediate-release composition, or both, can be formulated to mimic the blood plasma profile of an additional drug, as described in clinical documents recorded by GBL, or as required by the GBL. In other words, the slow and / or immediate release portions of the modified release composition can release at least one additional drug at the same rate as the available

- 16,007156 in the sale of the composition, thus providing a therapeutically effective amount of an additional drug.

The modified release composition may be in the form of bilayer tablets, capsules having a combination of beads or granules from the immediate release composition and a slow release composition or tablet in which the slow release composition is incorporated into a core that is coated with a layer of the immediate release composition. For the sake of illustration only, the invention will be described in detail in the context of a bilayer tablet.

The immediate release composition may include guaifenesin and various pharmaceutical additives such as lubricants, colorants, binders, polishing agents, surface active agents, preservatives, stabilizers, as described above and / or any other pharmaceutical additives known to those skilled in the art. In one embodiment, the immediate-release composition layer comprises at least one drug. In another embodiment, the immediate-release composition layer comprises at least two drugs. In a more preferred embodiment, the immediate-release composition comprises guaifenesin, microcrystalline cellulose, sodium starch glycolate and magnesium stearate. In another more preferred embodiment, the immediate release composition comprises guaifenesin, at least one additional drug, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium starch glycolate and magnesium stearate. In another preferred embodiment, the immediate-release composition may comprise about 47-58% guaifenesin, about 32-42% microcrystalline cellulose, about 3-8% sodium starch glycolate, and about 0.3-0.5% magnesium stearate by weight. In yet another preferred embodiment, the immediate-release composition comprises about 47-58% guaifenesin, about 3-5% of at least one of the additional drug, about 32-42% microcrystalline cellulose, about 2-5% hydroxypropylmethyl cellulose, about 3-8% sodium glycolate starch; and about 0.3-0.5% magnesium stearate by weight.

A bilayer tablet may be made according to any method known to those skilled in the art. The finished tablet comprises two parts pressed together so that the surface of each part represents the top or base of the tablet, or the finished tablet may include a core of a slow release composition that is coated with a layer of a slow release composition so that only the immediate release composition is outside. In a preferred embodiment, the two-layer tablet comprises two parts pressed together so that the surface of each part is exposed as the top or base of the tablet.

In a preferred method for preparing bilayer tablets, a slow release composition is prepared according to the wet granulation method or according to the dry granulation method as described above. An immediate release composition can be prepared by conventionally mixing guaifenesin with any pharmaceutical additives. If at least one additional drug is present, then, as described above, water may be added to the composition. In another preferred embodiment, appropriate amounts of guaifenesin OS. microcrystalline cellulose and sodium starch glycolate are homogenized in a 10 cc blender. feet for approximately 20 minutes Next, an appropriate amount of magnesium stearate is added to these ingredients, and the mixture is homogenized for another approximately 10 minutes to prepare an immediate release composition. Thereafter, portions of the slow release composition and the immediate release composition are compressed as a two-layer tablet in a tablet machine capable of forming two-layer tablets. In one embodiment, these tablets may be further coated with a protective film that quickly dissolves or disintegrates in the gastric juice.

Tablets can be prepared with any ratio of guaifenesin to at least one additional drug that provides a blood profile that demonstrates the corresponding therapeutic effect over longer periods of time. As indicated above, the additional drug may be present in an amount sufficient to mimic the blood serum profile of a commercially available drug composition and not exceed the maximum dose approved by ΕΌΆ for treatment, prophylaxis or improvement in a particular disease. In one embodiment, the ratio of the total amount of guaifenesin to at least one additional drug is about 1: 1-30: 1, more preferably about 1: 1-25: 1, and most preferably about 20: 1 by weight. Alternatively, the ratio is about 2: 1-15: 1, and more preferably, the ratio of guaifenesin to at least one additional drug is about 8: 1-12: 1 by weight. If present in the immediate release layer, the amount of at least one additional drug should be sufficient to match the release profile of the additional drug in the composition of the sustained release profile.

- 17 007156

In a preferred embodiment, the tablets are formulated with any ratio of guaifenesin to pseudoephedrine that provides a blood profile demonstrating an appropriate therapeutic effect over longer periods of time. As indicated above, pseudoephedrine is present in an amount sufficient to mimic the blood serum profile of a commercially available drug composition and not exceed the maximum dose approved by ΡΌΆ for the treatment, prophylaxis, or improvement in a particular disease. In one embodiment, the ratio of total guaifenesin to pseudoephedrine is about 1: 1-30: 1, more preferably about 1: 1-25: 1, and more preferably about 20: 1 by weight. Alternatively, the ratio of guaifenesin to pseudoephedrine is approximately 8: 1-12: 1 by weight. In another embodiment, pseudoephedrine is present only in the immediate release layer.

In a preferred embodiment, the tablets are formulated with any ratio of guaifenesin to dextromethorphan that provides a blood profile demonstrating the corresponding therapeutic effect over longer periods of time. As indicated above, dextromethorphan is present in an amount sufficient to mimic the blood serum profile of a commercially available drug composition and not exceed the maximum dose approved by ΡΌΑ for treatment, prophylaxis, or improvement in a particular disease. In one embodiment, the ratio of the total amount of guaifenesin to dextromethorphan is about 1: 1-30: 1, more preferably about 1: 1-25: 1, and more preferably about 20: 1 by weight. Alternatively, the ratio of guaifenesin to dextromethorphan is about 8: 1-12: 1 by weight.

Tablets can be prepared in any ratio of a slow-release composition to an immediate-release composition that provides a blood profile demonstrating an appropriate therapeutic effect over longer periods of time. In one embodiment, the bilayer tablets comprise guaifenesin distributed within the slow release composition and the immediate release composition, wherein the ratio of guaifenesin in SV to guaifenesin in ΙΒ is about 1: 1-20: 1, more preferably about 1: 1-1: 15 by weight ; preferably a ratio of about 3: 2-11: 1 or more. Preferably, the ratio of guaifenesin distributed within the slow release composition to the immediate release composition is about 5: 1-9: 1 by weight, respectively. For example, in a 1200 mg sustained release two-layer tablet of guaifenesin, there may be approximately 200 mg of guaifenesin in the immediate-release layer and approximately 1000 mg of guaifenesin in the slow-release layer.

Tablets may be prepared with at least one additional drug only within the slow release composition or with the additional drug only in the immediate release composition. Optionally, tablets may be prepared with at least one additional drug distributed within the slow release composition and the immediate release composition. In one embodiment, two-layer tablets comprise an additional drug distributed within the slow release composition and the immediate release composition, wherein the ratio of the additional drug in the SV to the additional drug in ΙΒ is about 1: 1-20: 1, more preferably about 1: 1 -1: 15 by weight; preferably a ratio of about 3: 2-9: 1; and more preferably a ratio of about 3: 1-4: 1 by weight, respectively. Alternatively, the weight ratio for the additional drug in the sustained release composition to the immediate release composition is about 4: 1-1: 1, more preferably about 1: 1-2: 1.

In one preferred embodiment, in the manufacture of a two-layer, 1200 mg sustained release tablet of guaifenesin, approximately 105 kg of guaifenesin ES. approximately 2.5 kg of the E10M metocel, approximately 1.25 kg of the 974P carbopol and approximately 0.333 kg of the dye EtegaI Sgsssp Bake or TE&C B1ie Νο. 1 homogenize in a mixer RK, with a capacity of 10 cubic meters ft. (0.283 m ³ ) for approximately 20 minutes. After that, approximately 0.6 kg of magnesium stearate is added and homogenized for approximately 10 minutes to prepare a slow release composition. Approximately 21 kg of ES guaifenesin, approximately 11.75 kg of microcrystalline cellulose and approximately 3 kg of sodium starch glycolate are homogenized in a R.K. mixer with a capacity of 3 cubic meters. feet for about 20 minutes. After that, approximately 0.1 kg of magnesium stearate can be added and homogenized for approximately 10 minutes to prepare an immediately releasing composition. Further, these two compositions can be pressed in order to obtain a two-layer tablet, in which approximately 75% of each tablet can be a slow-release composition and about 25% of each tablet can be an immediate-release composition. The tablets may be of any dosage strength, any size or shape. In a preferred embodiment, 1200 mg tablets are round, approximately 5/8 inches (1.587 cm) in diameter, approximately 0.28-0.31 inches (0.71-0.79 cm) in thickness, weigh approximately 1.46 g and have a range hardness of approximately 15-40 ZSI. In another preferred embodiment, a tablet

- 18,007156 ki in 600 mg round, approximately 1/2 inch (1.27 cm) in diameter, approximately 0.218-0.230 inches (0.56-0.58 cm) in thickness, weigh approximately 0.729 g and have a hardness range of approximately 12 -30 §si.

In another preferred embodiment of the invention, in the manufacture of a 1200 mg two-layer sustained release tablet of guaifenesin, approximately 101 kg of guaifenesin OS, approximately 4.5 kg of at least one of an additional drug such as dextromethorphan, approximately 5 kg of metocel E10M, approximately 1.5 kg of carbopol 974P and about 0.04 kg of dye ΡΌ & Ο B1ie Νο. 1 homogenize in a mixer with a capacity of 10 cubic meters. ft. (0.283 m ³ ) for approximately 12 minutes. After that, approximately 29 kg of water was added and the mixture was homogenized for an additional 10 minutes and then dried. After that, 1 kg of magnesium stearate can be added and homogenized for approximately another 10 minutes to prepare a slow release composition. Approximately 45.6 kg of guaifenesin, approximately 3.6 kg of at least one additional drug such as dextromethorphan, approximately 40.32 kg of microcrystalline cellulose and approximately 3 kg of starch sodium glycolate are homogenized in a 3 cc blender. feet (49.16 cm ³ ) for approximately 12 minutes. After that, approximately 36 kg of water is added and the mixture is homogenized for an additional 10 minutes and then dried. After that, approximately 0.48 kg of magnesium stearate can be added and homogenized for approximately another 10 minutes to prepare an immediate release composition. Further, these two compositions can be pressed in order to obtain a two-layer tablet, in which approximately 75% of each tablet can be a slow-release composition and about 25% of each tablet can be an immediate-release composition. The tablets may be of any dosage strength, any size or shape. In a preferred embodiment, 1200 mg tablets are round, approximately 5/8 inches (1.587 cm) in diameter, approximately 0.31-0.34 inches (0.79-0.86 cm) in thickness, weigh approximately 15.3 g and have a range hardness of approximately 15-35 8SI. In another preferred embodiment, 600 mg tablets are round, about 1/2 inch (1.27 cm) in diameter, about 0.22-0.26 inch (0.56-0.66 cm) in thickness, weigh about 7, 65 g and have a hardness range of approximately 15-65 8 SI.

The immediate release portion of the bilayer tablet composition is formulated to dissolve in low pH aqueous media such as gastric juice and quickly release guaifenesin contained in that portion of the tablet. This leads to rapid bioaccumulation of a high concentration of guaifenesin. As shown below, in example 6 and in FIG. 9 and 10, the immediate-release portion of the bilayer tablet composition provides a maximum plasma concentration (C _max ) and a maximum plasma concentration time (T _max ) equivalent to that obtained with C _max when the first of three doses of the standard immediately-releasing bilayer tablet composition containing one third of the amount of guaifenesin dosed every four hours for a period of 12 hours

Gels with immediate-release portions entering a low pH environment allow the delayed-release portion of the tablet to move into the intestinal tract. In the intestine, the gel-like, slow-release portion enters a medium with a higher pH value, as a result of which the gel slowly dissolves and thus guaifenesin diffuses and is washed out of the gel-like matrix. This leads to controlled bioaccumulation over a longer period of time (i.e., 8-12 or more hours) and allows for a longer therapeutic effect. As shown in Example 6 and FIG. 9 and 10, the half-life of the modified two-layer tablet is increased by more than 3 hours and the tablet has an AISinf (region at a plasma concentration against the time curve from 0 to infinity) of more than 8000 h-ng / ml (yt-pd / nE).

As shown in Example 7 and FIG. The 11 two-layer tablets of the present invention showed an unexpected result in that a 600 mg tablet had a T _max equivalent to a 1200 mg tablet, and C _max and AIS _in about half the 1200 mg tablet. Thus, without adjusting or changing the composition of the slow release bilayer tablet composition, the low guaifenesin dosage tablet of the present invention provides a plasma concentration profile that is approximately directly proportional to the plasma concentration profile of the higher guaifenesin dosage tablet. As further shown in Example 7 and FIG. 11 two-layer tablets showed the following effect: C _max and AIS _in tablets of 1200 mg administered to fasting volunteers, and C _max and AIS _in tablets of 1200 mg administered to very fatty food volunteers were approximately equivalent. Thus, being approximately equally effective for a patient with an empty or full stomach, the two-layer tablet of the present invention exhibits low sensitivity with respect to food effects. Similar results were obtained for combination compositions, for example as described in examples 8-21.

Several combination compositions were compared with commercially available drugs also for bioaccumulation. Example 8 shows three batches of 1200 mg guaifenesin / 60 mg dextromethorphan hydrobromide tablets that were dissolved to determine the amount of time-released dextromethorphan hydrobromide. In general, the compositions contained 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide and were studied over a period of 12 hours. The amount released

- 19 007156 dextromethorphan hydrobromide was determined as the weight percentage of dissolved dextromethorphan from the total weight of dextromethorphan to dissolution. After 1 h, approximately 46-47% of dextromethorphan was dissolved. After 2 hours, approximately 59-60% was dissolved, after 6 hours, 73-76% was dissolved, and after 12 hours, approximately 86-89% of dextromethorphan was dissolved by weight. Thus, the compositions of this invention reproducibly release dextromethorphan over time (see FIG. 12). Example 9 shows the bioaccumulation of ίη νίνο in the sustained release of guaifenesin with dextromethorphan.

Various combinations of the guaifenesin / pseudoephedrine composition were also investigated to determine their dissolution rate and bioaccumulation. Examples 10 and 11 present the compositions of guaifenesin and pseudoephedrine in a sustained release portion of a bilayer tablet. The results show that the combination of drugs in the form of a separate tablet according to the methods of implementation of the present invention does not affect the rate of their dissolution and the profile of their release ίη νίνο.

Two prototypes from Example 12 showed the same release profiles of ίη νίίτο as Mucinex ™ (Mistech ™) and Sudafed® (ZibaGeb®) marketed. In particular, composition B (batch PB01-K61) ensured optimal bioaccumulation for both guaifenesin and pseudoephedrine and was therefore used in subsequent bioaccumulation studies.

Example 13 compares the combined products of guaifenesin / pseudoephedrine hydrochloride with a strength of 1200/120 mg, composition B (batch PB01-M65A2) with a strength of 600/60 mg, composition C (batch PB01A12A) with commercially available products Mucinex ™ (Mistech ™) and Sudafed® ( ZibaGeb®) 12 hours. A drug with a strength of 1200/120 mg turned out to be bioequivalent with respect to C _max and AISinf with a 90% confidence interval, which is in the range of 80-125%. Further, a 600/60 mg drug showed pharmacokinetics proportional to the dosage.

Example 14 compares the indicated Mucinex ™ (Mistech ™) and Sudafed® (ZibaGeb®) 12 hours with the tested composition (batch PB01-M65A3) with a strength of 1200/120 mg for steady state bioaccumulation after 11 days with a daily two-time regimen. When compared with these drugs, the test composition was bioequivalent (within the range of 80-125%, with a 90% confidence interval). Therefore, for both guaifenesin and pseudoephedrine, the established C _max and AIS _ZZ were bioequivalent.

Examples 15 and 17 compare the effect of very fatty foods for the specified reference compositions and combination compositions of the present invention. The test composition (batch PB01-M65) was not bioequivalent to Cmax for guaifenesin, but was bioequivalent to the pseudoephedrine portion compared to the reference. However, AISinf was bioequivalent for both guaifenesin and pseudoephedrine within the range of 80-125%.

Example 16 compares a unit dose-dependent bioaccumulation and the interaction potential of guaifenesin and pseudoephedrine, administered as Mucinex ™ (Mistech ™) and Sudafed® (ZibaGeb®) 12 h, alone or in combination. The results show that in this case, the pharmacokinetics of guaifenesin and pseudoephedrine does not change relative to AISinf and C _max in the presence or absence of each other (ratio within 80-125%). This further confirms the results of other examples that demonstrate the bioequivalence of the combined compositions of the invention.

Example 18 compares the bioaccumulation of guaifenesin and dextromethorphan from an experimental composition containing guaifenesin and dextromethorphan in the same amount as the reference preparation. The pharmacokinetics of guaifenesin and dextromethorphan did not change in the presence of another component, and the pharmacokinetics of dextromethorphan was linear in the studied range.

Example 19 compares the relative bioaccumulation of guaifenesin and dextromethorphan from an experimental composition containing guaifenesin and dextromethorphan in the same amount as the reference preparation. Guaifenesin in the experimental tablet was clearly bioequivalent to the reference drug Mucinex (Mistech) in terms of C _max , AIS _o-1 or AISinf. Dextromethorphan hydrobromide in an experimental tablet also was bioequivalent to the parameters C _max, AIS _of-1 or AiS _yn f as at a dose of dextromethorphan hydrobromide 30 mg every 6 hours, and at a dose of 20 mg every 4 hours.

Example 20 compares the relative bioaccumulation of guaifenesin and dextromethorphan from an experimental composition containing guaifenesin and dextromethorphan after a patient has consumed very fatty foods compared to subsequent nightly starvation. Eating did not have any effect on the absorption of guaifenesin from the experimental tablet. Eating affected the absorption rate of dextromethorphan from the tablet of the experimental composition (a small increase in absorption rate), but not the extent of absorption.

Example 21 compares the relative bioaccumulation of guaifenesin and dextromethorphan from an experimental composition containing guaifenesin and dextromethorphan in the same amount as the reference preparation. Guaifenesin in the experimental tablet was bioequivalent to the reference preparation Mucinex (Mistech) in terms of C _max and AIS _ZZ in the range of 80-125%. Dextromethorphan hydrobromide in the experimental tablet was bioequivalent in terms of C _max , and AIS _ZZ within

- 20 007156

80-125%, both at a dose of 30 mg of dextromethorphan hydrobromide every 6 hours, and at a dose of 20 mg every 4 hours

These studies indicate that the compositions of this invention provide systemic drug levels over a 12-hour period. In addition, these studies show bioequivalence of the combined compositions.

Comparison with drugs approved by the Food and Drug Administration (ΕΌΑ)

When using RIA approved drugs, the slow release composition, alone or in combination with the immediate release composition, can be formulated to mimic the plasma profile of guaifenesin and optionally additional drug (s), as described in the clinical documents recorded by the RIA, or as required by the RIA. This information can be found at: 1Shr: // \ y \ y \ u.Gba.dow / escape / Go1upba / 2002 / 21282_Mis1peh.1! T, which is hereby incorporated by reference in its entirety. For example, a single dose of an immediate-release tablet of 400 mg has a C _{max of} 2.463 ± 1033, T _{max of} 5, AIC _0-12 8.382 ± 3.282, AISinf 8.529 ± 3.362, and T _1/2 0.78 ± 0.09. Alternatively, multiple doses of immediate release tablets have 400 mg C _max 2.278 ± 791 T _max 5 AIS _0- February ₁ 7,751 ± 2.697, C _{"[1 [| 0112} ± 52 and ₂₁₃₇ ± Smin1 98. Preferably, the compositions provide a maximum plasma concentration (C _max ) and / or a maximum plasma concentration time (T _max ) equivalent to that obtained with C _max when the first of three doses of a standard immediate-release composition having one third of the amount of guaifenesin is dosed every four hours for a period of 12 hours. In other words, the slow release composition releases guaifenesin and at least one additional drug at a rate similar to that available in even compositions, thus providing a therapeutically effective amount of both drugs. Alternatively, the parameters can be calculated using any of the following parameters or a combination thereof: C _max , C _min , T _max , AISinf, AIS _o-1 , AIS ₃₃ and T _1/2 . Unless otherwise indicated, all references to AIS _0-1 in the description and in the claims should be related to data that correspond to a time (!) Of 24 hours. The parameters can also be calculated from the data of the study ίη у1уо, such as those presented here, where equivalence defined as an average value, and a range of 80-125% with a 90% confidence level and / or one standard deviation from the average. Alternatively, the parameters can also be calculated from research data ίη у1уо, such as those presented here, where equivalence is defined as the average value and the range is 80-125% with a 90% confidence level and / or one standard deviation from the mean. Due to the extreme variability of dextromethorphan, as recognized by the RIA, and the variability inherent in plasma serum levels, equivalence is determined at picogram levels from the average, the range is 50-150%, more preferably the equivalence is determined from the average, the range is 60-140% and most preferably the equivalence is determined from the average, a range of 80-125% with a 90% confidence level. FIG. 31 and 32 show specification ranges for various batches of the composition of the invention.

In addition, Stach for guaifenesin, or the additional drug (s), or for both, preferably lies between 80 and 125% of an approved RIA of average size, more preferably between 90 and 115%, and most preferably between 95 and 115%. These ranges should not vary proportionately, that is, depending on the wording, the average value may, for example, preferably be between 90 and 125% of the approved RIA average value. Alternatively, the lower C _max limit 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 composition. The upper limit of C _max 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 composition. For a 1200 mg tablet, the range is preferably between 1000 and 3750 ng / ml, 1200 and 3500 ng / ml, 1350 and 3000 ng / ml and 1450 and 2750 ng / ml. For a 600 mg tablet, the range is preferably between 320 and 1875 ng / ml, 400 and 1500 ng / ml, 500 and 1375 ng / ml, and finally 625 and 1250 ng / ml.

Alternatively, the lower C _max limit 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 composition. The upper limit of 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 composition. For a 120 mg tablet, the range is preferably between 150 and 500 ng / ml, 175 and 500 ng / ml, 200 and 450 ng / ml, 250 and 400 ng / ml, and finally 300 and 375 ng / ml. For a 60 mg tablet, the range is preferably between 75 and 250 ng / ml, 88 and 250 ng / ml, 100 and 225 ng / ml, 125 and 200 ng / ml, and finally 150 and 188 ng / ml.

Alternatively, the lower C _max limit for dextromethorphan is preferably greater than 3840 pg / ml, more preferably 5500 pg / ml, more preferably 6600 pg / ml, more preferably 7000 pg / ml, more preferably 7700 pg / ml, more preferably 8000 pg / ml more prefer

- 21 007156 specifically 8800 pg / ml, more preferably 9900 pg / ml, and most preferably 10,000 pg / ml, depending on the composition. The upper C _max limit for dextromethorphan is preferably less than 22500 pg / ml, more preferably 16500 pg / ml, more preferably 15400 pg / ml, more preferably 14300 pg / ml depending on the composition. For a 60 mg tablet, the range is preferably between 9600 and 15000 pg / ml, 10800 and 13500 pg / ml, 10800 and 12000 pg / ml, and finally 12000 and 13500 pg / ml. For a 30 mg tablet, the range is preferably between 7200 and 11250 pg / ml, 8100 and 10125 pg / ml, 8100 and 9000 pg / ml, and finally 9000 and 10125 pg / ml. In an alternative embodiment, the lower C _max limit for dextromethorphan is preferably greater than 1300 pg / ml, more preferably 1550 pg / ml, more preferably 1860 pg / ml, more preferably 2170 pg / ml, more preferably 2480 pg / ml and most preferably 2790 pg / ml depending on the composition. The upper limit of Smake for dextromethorphan is preferably less than 5400 pg / ml, more preferably 4650 pg / ml, more preferably 4350 pg / ml, more preferably 4000 pg / ml, more preferably 3750 pg / ml and most preferably 3400 pg / ml, depending from the composition.

C _mines is another aspect that various slow release drugs found on the market rarely match. The compositions of this invention provide C, _{w [|} . which maintains such therapeutic efficacy for at least 10 hours, more preferably 12 hours, and most preferably 14 or more hours. In addition, Cmin for guaifenesin, the additional drug (s), or for both, preferably between 80 and 125% of the approved ΡΌΑ average value, more preferably between 90 and 115% and most preferably between 95 and 115%. These ranges should not vary proportionately, i.e. the average value may be, for example, preferably between 90 and 125% of the approved ΡΌΑ average value, depending on the composition. Alternatively, the lower limit of Cmin 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 composition. The upper limit of Cmin 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 composition. The C _min range for both a 1200 mg tablet and a 600 mg tablet can be selected from 50 and 150 ng / ml, 50 and 125 ng / ml, 60 and 125 ng / ml, 70 and 125 ng / ml, 80 and 125 ng / ml, between 35 and 75 ng / ml, 40 and 70 ng / ml, 45 and 65 ng / ml and 50 and 60 ng / ml.

Alternatively, the lower limit of Cmin 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 composition. The upper limit of Cmin 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 composition. The Cmin range for both a 120 mg tablet and a 60 mg tablet can be selected from 75 and 300 ng / ml, 100 and 250 ng / ml, 125 and 225 ng / ml, 150 and 200 ng / ml.

Alternatively, the lower limit of Cmin for dextromethorphan is preferably greater than 1250 pg / ml, more preferably 1500 pg / ml, more preferably 1700 pg / ml, more preferably 2000 pg / ml and most preferably 2250 pg / ml. Alternatively, the upper C _min limit for dextromethorphan is preferably less than 3750 pg / ml, more preferably 3500 pg / ml, more preferably 3250 pg / ml, more preferably 3000 pg / ml and most preferably 2750 pg / ml depending on the composition. Alternatively, the Cmin range for a 60 mg tablet may be selected from 7200 and 11250 pg / ml, 8100 and 10125 pg / ml, 8100 and 9000 pg / ml and 9000 and 10125 pg / ml. The C _min range for a 30 mg tablet can be selected from 5400 and 8400 pg / ml, 6075 and 7600 pg / ml, 6075 and 6750 pg / ml, and finally 6750 and 7600 pg / ml. In another embodiment, the lower limit of Cmin for dextromethorphan is preferably greater than 1050 pg / ml, more preferably 1250 pg / ml, more preferably 1450 pg / ml, more preferably 1650 pg / ml and most preferably 1850 pg / ml. The upper limit of Cmin for dextromethorphan is preferably less than 3150 pg / ml, more preferably 2950 pg / ml, more preferably 2700 pg / ml, more preferably 2500 pg / ml and most preferably 2300 pg / ml depending on the composition.

The compositions of this invention provide T _max for guaifenesin, additional drug (s), or both, which preferably lies between 80 and 125% of the approved ΡΌΑ average value, more preferably between 90 and 115% and most preferably between 95 and 115%.

These ranges should not vary proportionately, i.e. the average value may, for example, preferably be between 90 and 125% of the approved ΡΌΑ average value, depending on the composition. Alternatively, the lower limit T _max 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 composition. The upper limit T _max 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 composition. The T _max range can also be selected between 0.6 and 3.0 hours, 0.8 and 2.5 hours, 0.9 and 2.25 hours, 1.0 and 2 hours, and finally 1.1 and 2 hours

Alternatively, the lower T _max limit 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

- 22,007156 respectfully 4.75 hours depending on the composition. The upper limit 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 composition. The T _max range can also be selected between 3.75 and 9.0 hours, 4.0 and 8.5 hours, 4.25 and 8.0 hours, 4.5 and 7.5 hours, and finally 4.75 and 7.5 hours

Alternatively, the lower T _max limit 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 composition. The upper limit of T _max 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 composition. For a 60 mg tablet, a T _max range can also be selected between 6.2 and 9.7 hours, 6.7 and 8.8 hours, 6.7 and 7.75 hours and 7.75 and 8.8 hours. Similarly , for a 30 mg tablet, the T _max range can be selected between 4.6 and 7.25 hours, 5.2 and 6.5 hours, 5.2 and 5.8 hours, and finally 5.8 and 6.5 h

The compositions of the present invention for guaifenesin, supplemental drug (s), or both provide AISinf, which lies preferably between 80 and 125% of the approved ΕΌΑ average value, more preferably between 90 and 115% and most preferably between 95 and 115%. These ranges should not vary proportionately, i.e. the average value may be, for example, preferably between 90 and 125% of the approved ΕΌΑ average value, depending on the composition. Alternatively, the lower limit of AIS _in f for guaifenesin is preferably greater than 4000 h-ng / ml, more preferably 5000 h-ng / ml, more preferably 5500 h-ng / ml and most preferably 6000 h-ng / ml, depending on the composition. The upper limit of APSyns for guaifenesin is preferably less than 12,500 h-ng / ml, more preferably 10,000 h-ng / ml, more preferably 9,500 h-ng / ml and most preferably 9,000 h-ng / ml, depending on the composition. For a 1200 mg tablet, the AISinf range can be selected from 4,000 and 12,500 h-ng / ml, 5,000 and 10,000 h-ng / ml, and 5,500 and 9,500 h-ng / ml and finally 6,000 and 9,000 h-ng / ml. For 600 mg tablets AiS _yn range f may be selected from the 2000 and 6250 chng / ml, 2500 and 5000 chng / ml, 2250 and 4750 chng / ml, and 3000 and 4500 chng / ml.

Alternatively, the lower limit of AISinf for pseudoephedrine is preferably greater than 2500 hng / ml, more preferably 2800 h-ng / ml, more preferably 3500 h-ng / ml, and most preferably 3750 h-ng / ml, depending on the composition. The upper limit of AISinf for pseudoephedrine is preferably less than 6000 h-ng / ml, more preferably 5800 h-ng / ml, more preferably 5500 h-ng / ml and most preferably 5000 h-ng / ml, depending on the composition. For a 120 mg tablet, AiSinf can be selected from 2500 and 6000 h-ng / ml, 2800 and 5800 h-ng / ml, 3500 and 5500 h-ng / ml and 3750 and 5000 h-ng / ml. For tablets of 60 mg AiS _yn f may be selected from the 1250 and 3000 chng / ml 1400 and 2900 chng / ml 1750 and 2750 chng / mL and finally, 1875 and 2500 chng / ml.

Alternatively, the lower limit of AIS _in f for dextromethorphan is preferably greater than 55200 h-ng / ml, more preferably 145000 h-ng / ml, more preferably 174000 h-ng / ml, more preferably 192000 h-ng / ml, more preferably 203000 h ng / ml, more preferably 216,000 h-ng / ml, more preferably 232,000 h-ng / ml, more preferably 240,000 h-ng / ml and most preferably 261,000 h-ng / ml, depending on the composition. The upper limit of AISinf for dextromethorphan is preferably less than 587500 h-ng / ml, more preferably 435000 h-ng / ml, more preferably 405000 h-ng / ml, more preferably 400000 h-ng / ml, more preferably 377000 h-ng / ml more preferably 360,000 h-ng / ml, more preferably 348,000 h-ng / ml and most preferably 320,000 h-ng / ml depending on the composition. For a 60 mg tablet, AiSinf can be selected from between 256,000 and 400,000 h-ng / ml, 288,000 and 360,000 h-ng / ml, 288,000 and 320,000 h-ng / ml and, finally, 320,000 and 360,000 h-ng / ml. For a 30 mg tablet, AISinf can be selected from 192,000 and 300,000 h-ng / ml, 216,000 and 270,000 h-ng / ml, 216,000 and 240,000 h-ng / ml and, finally, 240,000 and 270,000 h-ng / ml. In another embodiment, the lower limit of AISinf for dextromethorphan is preferably greater than 15,000 h-ng / ml, more preferably 18,000 h-ng / ml, more preferably 21,000 h-ng / ml, more preferably 24,000 h-ng / ml and most preferably 27,000 h- ng / ml depending on the composition. The upper limit of APS _inf for dextromethorphan is preferably less than 46900 h-ng / ml, more preferably 45000 h-ng / ml, more preferably 42000 h-ng / ml, more preferably 39000 h-ng / ml, more preferably 36000 h-ng / ml, and most preferably 33,000 h-ng / ml, depending on the composition.

The compositions of this invention provide AIS _0-1; for guaifenesin, the complementary drug (s), or both, which preferably lies between 80 and 125% of the approved EEA average value, more preferably between 90 and 115%, and most preferably between 95 and 115%. These ranges should not vary proportionately, i.e. the mean value may, for example, preferably be between 90 and 125% of the EEA approved mean value, depending on the composition. Alternatively, the lower limit of AIS is _0-1; for guaifenesin, preferably more than 3200 h-ng / ml, more preferably 3700 h-ng / ml, more preferably 4000 h-ng / ml, and most preferably 4500 h-ng / ml, depending on the composition. The upper limit of AIS _0-1 for guaifenesin is preferably less than 11250 h-ng / ml, more preferably 10500 h-ng / ml, more preferably 9500 h-ng / ml, more preferably 9000 h-ng / ml and most preferably 8500 h ng / ml depending on the composition. For a 1200 mg tablet, AIS _0-1 can be selected from 3200 and 11250 h-ng / ml, 3700 and 10500 h-ng / ml,

- 23 007156

4000 and 9500 h-ng / ml, 4250 and 9000 h-ng / ml, and finally 4500 and 8500 h-ng / ml. For a 600 mg tablet, LIS _0-1 can be selected from 1600 and 5625 h-ng / ml, 1850 and 5250 h-ng / ml, 2000 and 4750 h-ng / ml, 2125 and 4500 hng / ml, and finally 2250 and 4250 h-ng / ml.

Alternatively, the lower limit of LIS _0-1 for pseudoephedrine is preferably greater than 2000 hng / ml, more preferably 2200 h-ng / ml, more preferably 2500 h-ng / ml and most preferably 2800 h-ng / ml, depending on the composition. The upper limit of LIS is ₀ . ₁ for pseudoephedrine, preferably less than 6000 h-ng / ml, more preferably 5750 h-ng / ml, more preferably 5500 hng / ml, more preferably 5250 h-ng / ml and most preferably 5000 h-ng / ml, depending on the composition . For a tablet of 120 mg LIS ₀ . ₁ can be selected from 2000 and 6000 h-ng / ml, 2200 and 5750 hng / ml, 2500 and 5500 h-ng / ml, 2700 and 5250 h-ng / ml and finally 2800 and 5000 h-ng / ml . For a 60 mg tablet, LIS _0-1 can be selected from 1000 and 3000 h-ng / ml, 1100 and 2875 h-ng / ml, 1250 and 2750 h-ng / ml, 1350 and 2625 h-ng / ml and, finally, 1400 and 2500 h-ng / ml.

Alternatively, the lower limit of LIS _0-1 for dextromethorphan is preferably greater than 59,000 h-ng / ml, more preferably 119,000 h-ng / ml, more preferably 143,000 h-ng / ml, more preferably 162,000 h-ng / ml, more preferably 166,000 h-ng / ml, more preferably 182,000 h-ng / ml, more preferably 190,000 h-ng / ml, more preferably 202,000 h-ng / ml and most preferably 214,000 h-ng / ml, depending on the composition. The upper limit of AIS _0- for dextromethorphan is preferably less than 475,000 h-ng / ml, more preferably 360,000 h-ng / ml, more preferably 337,500 h-ng / ml, more preferably 333,000 h-ng / ml, more preferably 309,000 h- ng / ml, more preferably 300,000 h-ng / ml, more preferably 286,000 h-ng / ml, more preferably 270,000 h-ng / ml and most preferably 262,000 h-ng / ml, depending on the composition. For a 60 mg tablet, LIS _0-1 can be selected from 216,000 and 337,500 h-ng / ml, 243,000 and 300,000 h-ng / ml, 243,000 and 270,000 h-ng / ml and, finally, 270,000 and 300,000 h-ng / ml For a 30 mg tablet, LIS _0-1 can be selected from 162,000 and 250,000 h-ng / ml, 182,000 and 230,000 h-ng / ml, 182,000 and 202,000 h-ng / ml and finally 202,000 and 230,000 h-ng / ml In another embodiment, the lower limit of LIS _0-1 for dextromethorphan is preferably greater than 15,000 h-nanograms / ml, more preferably 18,000 h-ng / ml, more preferably 21,000 h-ng / ml, more preferably h-ng / ml and most preferably 27000 h-ng / ml depending on the composition. The upper limit of LIS is ₀ . ₁ for dextromethorphan, preferably less than 47300 hg / ml, more preferably 45000 h-ng / ml, more preferably 42000 h-ng / ml, more preferably 39000 h-ng / ml, more preferably 36000 h-ng / ml and most preferably 33000 h-ng / ml depending on the composition.

The compositions of the present invention for guaifenesin, an additional preparation (s), or both provide LIS _ss , which preferably lies between 80 and 125% of the approved EEL average value, more preferably between 90 and 115% and most preferably between 95 and 115%. These ranges should not vary proportionately, i.e., the average value may, for example, preferably be between 90 and 125% of the EEL-approved average value, depending on the composition. Alternatively, the low end of LIS _zs for guaifenesin is preferably greater than 5000 h-ng / ml, more preferably 5600 h-ng / ml, more preferably 6000 h-ng / ml and most preferably 6500 h-ng / ml, depending on the composition. The upper limit of LIS _zs for guaifenesin is preferably less than 9000 h-ng / ml, more preferably 8750 h-ng / ml, more preferably 8250 h-ng / ml and most preferably 8000 h-ng / ml, depending on the composition. LIS _zz for a 1200 mg tablet can be selected from 5000 and 9000 h-ng / ml, 5600 and 8750 h-ng / ml, 6000 and 8000 h-ng / ml, and finally 6500 and 8250 h-ng / ml. LIS _zs for a 600 mg tablet can be selected from 2500 and 4500 h-ng / ml, 2800 and 4375 h-ng / ml, 3000 and 4000 h-ng / ml, and finally 3250 and 4125 h-ng / ml.

Alternatively, the lower LISf limit for pseudoephedrine is preferably greater than 2100 hng / ml, more preferably 2400 hg-ng / ml, more preferably 2650 h-ng / ml, and most preferably 2800 h-ng / ml, depending on the composition. The upper limit of LIS _zs for pseudoephedrine is preferably less than 5500 h-ng / ml, more preferably 5000 h-ng / ml, more preferably 4500 hng / ml and most preferably 4000 h-ng / ml, depending on the composition. LIS _zz for a 120 mg tablet can be selected from 2 and 5500 h-ng / ml, 2400 and 5000 h-ng / ml, 2650 and 4500 h-ng / ml and finally 2800 and 4000 h-ng / ml. LIS _zs for a 60 mg tablet can be selected from 1050 and 2250 h-ng / ml, 1200 and 2500 hng / ml, 1325 and 2250 h-ng / ml, and finally 1400 and 2000 h-ng / ml.

Alternatively, the lower limit of LIS _zs for dextromethorphan is preferably greater than 87,750 cng / ml, more preferably 105,000 h-ng / ml, more preferably 120,000 h-ng / ml, more preferably 132,000 h-ng / ml, more preferably 140,000 h-ng / ml and most preferably 158,000 cng / ml, depending on the composition. The upper limit of LIS _zs for dextromethorphan is preferably less than 263,000 h-ng / ml, more preferably 245,000 h-ng / ml, more preferably 228,000 hng / ml, more preferably 220,000 h-ng / ml, more preferably 210,000 h-ng / ml, more preferably 197,000 h-ng / ml; and most preferably 193,000 h-ng / ml, depending on the composition. LIS _zs for a 60 mg tablet can be selected from 140,000 and 220,000 h-ng / ml, 157,500 and 197,000 h-ng / ml, 157,500 and 175,000 h-ng / ml and finally 175,000 and 197,000 h-ng / ml. LIS _zs for a 30 mg tablet can be selected from 105,000 and 165,000 h-ng / ml, 120,000 and 149,000 h-ng / ml, 120,000 and 132,000 h-ng / ml and finally 132,000 and 149,000

- 24,007156 h-ng / ml. In another embodiment, the lower limit of AIS ₃₃ for dextromethorphan is preferably greater than 19000 h-ng / ml, more preferably 22800 h-ng / ml, more preferably 26600 h-ng / ml, more preferably 30500 h-ng / ml and most preferably 34000 h ng / ml depending on the composition. The upper limit of AIS ₃₃ for dextromethorphan is preferably less than 57000 h-ng / ml, more preferably 53000 h-ng / ml, more preferably 49500 h-ng / ml, more preferably 45600 hng / ml and most preferably 41800 h-ng / ml depending on the composition.

The compositions of the present invention for guaifenesin, the complementary drug (s), or both provide T _1/2 , which lies preferably between 80 and 125% of the approved ΓΌΑ average value, more preferably between 90 and 115% and most preferably between 95 and 115%. These ranges should not vary proportionately, i.e. the average value may be, for example, preferably between 90 and 125% of the approved ΓΌΑ average value, depending on the composition. Alternatively, the lower limit of T _1/2 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

I, 4 hours, depending on the wording. The upper limit of 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. T _1/2 for a 1200 mg tablet can be selected between 0.7 and 7.25 hours, 0.9 and 6.0 hours, 1.1 and 5.0 hours, 1.3 and 3.5 hours, and finally, 1.4 and 3.5 hours. T _1/2 for a 600 mg tablet can be selected between 0.35 and 3.63 hours, 0.45 and 3.0 hours. 5.5 and 2.5 hours. 6.5 and 1.75 hours and finally 7.0 and 1.75 hours

Alternatively, the lower limit of T _1/2 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 composition. The upper limit of T _1/2 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 composition. T _1/2 for a 120 mg tablet can be selected between 3.2 and 8.0 hours, 3.6 and 7.5 hours, 4.0 and 7.0 hours, 4.2 and 6.25 hours, and finally 4.5 and 6.25 hours. T _1/2 for a 60 mg tablet can be selected between 1.60 and 4.0 hours, 1.80 and 3.75 hours, 2.0 and 3.5 hours , 2.1 and 3.13 hours, and finally 2.25 and 3.13 hours.

Alternatively, the lower limit of T _1/2 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 composition. The upper limit of 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 composition. T _1/2 for a 60 mg tablet can be selected between 9.4 and 14.7 hours, 10.6 and

13.2 hours, 10.6 and 11.75 hours, and finally 11.75 and 13.2 hours. T _1/2 for a 60 mg tablet can be selected between 7.0 and

II, 0 hours, 7.9 and 9.9 hours, 7.9 and 8.8 hours, and finally, 8.8 and 9.9 hours

Examples of other sustained release / immediate release compositions with and without additional drugs are discussed further in the examples below.

Examples

The invention is further illustrated by means of examples detailing the compositions and methods of the present invention. Professionals should be aware that there are various modifications both in materials and in the methods of the present invention, which are within the spirit and scope of this invention.

For ίη νίνο studies, for the analysis of samples, unless otherwise specified, the following general procedures were used. Blood samples were taken (5-10 ml, with the addition of sodium heparin as an anticoagulant) before dosing and after dosing at certain time intervals. After sampling, all blood samples were cooled and centrifuged for 30 minutes. The plasma was separated, transferred to a test tube of polypropylene, frozen at -20 ° C or lower and stored frozen until the drug was subsequently determined in it. After that, plasma samples were analyzed by the approved HPLC method. The obtained data on the change in plasma concentration over time were subjected to pharmacokinetic analysis using an isolated analysis with Vinnonlin 1.5 (Αίηηοηίίη 1.5).

Example 1

As needed, volunteers were provided with a relaxation period of at least seven days for excretion (during this period, the study patients did not take guaifenesin) until this group was followed by the next study group. Typically, subjects weighed within 15% of their ideal body weight, as determined by the 1983 City Life Chart.

A batch of slow-release guaifenesin tablets, B-οΐΝο, was prepared. 7BV-31GS, the following composition:

- 25 007156

Components Weight per tablet Guaifenesin OS 1260 mg Metocel E10M 30 mg Dye YeshegaM Steep Bake 4 mg Magnesium stearate 6.8 mg Opadri Υ-8-3-7413 (Oraigu Υ-8-3-7413) 13.01 mg

Another batch of slow-release guaifenesin tablets, ΕοΐΝο, was prepared. 7BV32ES, the following composition:

Components Weight per tablet Guaifenesin OS 1260 mg Metocel E10M 30 mg Carbopol 974P 15 mg Dye EtegaM Ogeep Bake 4 mg Magnesium stearate 6.8 mg Opadri Υ-8-3-7413 (Oradgu Υ-8-3-7413) 13.16 mg

Six tablets from a batch of 7BV-31ES and six tablets from a batch of 7BV-32ES were tested for the release of guaifenesin ίη ν ,ο using an acid / base dissolution method (slightly modified BG8P 23 / ΝΡ 18 <711>, using a drug release apparatus. 2). Six vessels for the dissolution of BG8R, calibrated according to the Hanson dissolution kit (Napzop), equipped with handles and blades, were filled with 675 ml Ο, ΙΝ of hydrochloric acid at 37.0 ° C. The bath and vessels were maintained at a temperature of 37.0 ± 0.5 ° C for a 12-hour dissolution test. The blades were set to rotate at a speed of 50 rpm./min and slowly descended into the vessels. After that, one tablet from a batch of 7BV-31 was dropped into each vessel.

After one hour, with two-hour test intervals, solution samples of 5 ml each were taken from each vessel, filtered through a 10-micron polyethylene filter into NRBS glass bottles. Immediately after the two-hour samples were taken, 225 ml of 0.2 M sodium orthophosphate was added to each vessel to bring the pH of the solution to approximately 6.8.

Dissolution occurred within an additional 10 hours; with an interval of 4, 8, 10, 12 hours, 2.0 ml samples were taken from each vessel. Filtered samples were then analyzed by NRBS to determine the percentage of released guaifenesin.

The same procedure for studying the dissolution process was performed for a batch of 7BV-32 RS. The batches showed dissolution profiles shown below and shown in FIG. 4.

Bo17BV-31

Vessel No. 1 hour 2 hours 4 hour 8 hour 10 hour 12 hour one 26 38 55 77 84 88 2 27 39 54 75 81 86 3 22 37 fifty 73 78 85 4 23 33 47 64 73 79 5 25 36 52 75 81 86 6 24 35 49 74 81 87 Average 24.5 36.3 51,2 73.0 79.7 85,2

-26007156

Bo1 7BV-32RS

Vessel No. 1 hour 2 hours 4 hour 8 hour 10 hour 12 hour one 25 36 42 54 59 64.0 2 24 35 42 55 61 66 3 26 38 45 59 65 69 4 24 35 42 54 60 65 5 24 36 43 54 59 64 6 23 34 38 fifty 55 59 Average 24.3 35.7 42.0 54.3 59.8 64.5

Both compositions showed a delayed release of guaifenesin over a period of 12 hours. In a Ο, ΙΝ hydrochloric acid solution, a batch of 7BV-32RS showed the same solubility as a batch of 7BV-31RS, however, in buffered solutions, a batch of 7BV-32RS, including E10M metocel ( Me11u1e1 E10M) and carbopol 974P (Sagoro1 974P) in a 2: 1 ratio, showed a statistically slower release than the batch 7BV-31RS, which included the E10M metocel (Me11use1 E10M), but not the 974P carbolopol (Sagoro1 974P). The slower dissolution rate of ίη νίίτο is expressed in a slower, more controlled release, which is accompanied by a longer action of the drug ίη νίνο, which is a favorable characteristic for pharmaceutical preparations containing a high concentration of the active component with a short half-life (for example, guaifenesin).

Example 2

In order to compare the dissolution profiles of batches 7BV-32RS and 7BV-31RS with the currently available dosage forms of guaifenesin, the dissolution processes of these preparations were studied. The solubility of one immediately releasing tablet of organidin ΝΚ (ΟΚΟΑΝΙϋΙΝ ΝΚ) and two slow-release tablets of humibid B.A. (NiM1VGO B.A.) and duratouss (ϋυΚΑΤυδδ) were investigated according to the method described in Example 1 above for batches 7BV-31RS and 7BV-32RS. Below are summarized results, which are also shown in FIG. 5.

Organidin ΝΚ (Og ^ apIt ΝΚ),% of released guaifenesin Gumibid B.A. (Ншп1Ы4 BA),% released guaifenesin Duratouss (Oigasterus),% released guaifenesin 1 hour one hundred 36 24 2 hours 103 51 35 4 hour 104 72 47 8 hour 103 91 75 10 hour 103 96 86 12 hour 105 one hundred 92

The immediate-releasing drug, organidin (OgdashsIp), released 100% of the guaifenesin it contained within the first hour after dissolution. Two commercially available sustained release dosage forms showed a slower release of guaifenesin. However, gumibid B.A. (Nipnib BA) and duratouss (Oigensus) both released guaifenesin more rapidly than batches of 7BV-31RS or 7BV-32RS, especially after an 8-hour interval.

Therefore, as gumibid B.A. (Nipnib BA) and duratouss (Oygris) show a higher release rate and, accordingly, a shorter therapeutic effect ίη νίνο.

Example 3

The behavior of ίη νίνο of the slow-release tablets of the 7BV-31RS batch and the 7BV-32RS batch of Example 1 was compared with the behavior of the ίη νίνο immediately releasing composition [organidine ΝΡ (OgdashsIp ΝΚ)]. The open-label study was conducted on 9 healthy volunteers aged 38 = 1 = 11.01 years, on average, in the range of 23 to 55 years. Subjects weighed 175.56 ± 24.22 pounds (79.63 ± 10.98 kg), in the range of 143-210 pounds (64.86-95.25 kg). One subject was female, and the rest was male. Each subject took a single dose of 1200 mg of 7BV-31RS, 7BV-32RS, or a commercially available immediate-release 400 mg tablet (3 doses every 4 hours).

The results of the pharmacokinetic analysis of the parameters are shown below and are shown in FIG. 6.

-27 007156

Subject Composition T _mak s, (hour) Smake (nanogram / ml) AIschs, (hour-nanogram / ml) T _w (hour) fox ^ (hour ng / ml) one 7BV-31RS 2.00 827.02 4817,20 4.64 6339.25 2 7BV-31RS 1,50 834.65 4695.89 2.71 5,291.71 3 7BV-31RS 1,50 802.44 4142.14 3.44 4728,33 4 7BV-32RS 0.75 625.48 3034.31 5.78 5134.35 5 7BV-32RS 1.00 1052.00 5872.46 5.99 8,298.33 6 7B-32RS 2.00 1372.00 7924.35 5.53 9557.78 7 Οι ^ πηϊάΐηΝΚ 0.50 2140.00 6921.94 0.86 7009.68 8 Step back ΝΚ 4.25 18.17.00 6598.26 0.73 6674.65 nine Og§apk1tR1K 0.50 2831.00 9389.76 0.81 9570.91 Average 7BV-31RS 1,67 821.37 4551.74 3,59 5453.10 Average 7BV-32RS 1.25 1016.49 5610.37 5.77 7663.49 Average Oops 1.75 2262.67 7636.65 0.80 7751.74 Ratio% 7BV-31RS / 1K 95.43 36.30 59.60 448.27 70.35 Ratio% 7ЕВ-32RSЛК 71.43 44.92 73.47 718.92 98.86

In subjects treated with the composition 7BV-32ES 1200 mg, the maximum plasma concentration of guaifenesin 1016 ng / ml was recorded at 1.25 h and f AiS _yn was 7663 hr-ng / ml. In subjects treated with the composition 7BV-31ES, maximum plasma guaifenesin concentrations 821 ng / ml was recorded at 1.67 h and f AiS _yn was 5453 hr-ng / ml. In subjects taking the immediate-releasing composition, organidin ΝΚ (Og ^ сссйп й), the maximum plasma concentration of guaifenesin 2263 ng / ml was recorded after 1.75 h (in 2 subjects, the maximum plasma concentration was recorded after 0.5 h, while after the first dose and the third maximum is reached after 0.25 hours after the second dose - 4 hours), and f _yn AiS chng was 7752 / ml. The two sustained release formulations showed sustained release with longer half-lives, 5.77 hours for the 7BB-32EC and 3.59 hours for the 7BB-31 EC, compared to 0.8 hours for the immediate-releasing composition, organidine Ог (Og ^ arsyp п) .

P1 compared to the immediate-releasing drug, organidin ΝΚ (Og ^ ссссйс ΝΚ), both compositions 7BB-32ES [together with the metocel E10М (Ме11юсе1 Е10М) and carbopol 974Р (Сапьоро1 974Р)] and 7БВ-31ЕС [together with the metocell Е10М1 Е10 (Е10) ], regulate the release of guaifenesin from the tablet. Composition 7BV 32RS-containing Methocel E10M (Me11yuse1) and Carbopol 974P (974P Sagoro1) in a ratio of 6: 1, had the longest half-life at 5.77 hours, and the highest between the two sustained release formulations indicator AiS _yn f · However, both the slow release formulations had a C _{max of} less than half the C _{max of the} immediately releasing preparation, organidin Ог (Og ^ acsInp ΝΚ).

P1 example 4.

A batch of three different time-release tablets of guaifenesin was prepared: ΐ) composition I - per 1200 mg of 8K; ίί) composition II - at 400 mg ΙΚ and 800 mg of 8 K; and ίίί) composition III - at 600 mg ΙΚ and 600 mg of 8K.

Layerless (sustained release) tablet.

Composition I

Components Weight per tablet Guaifenesin OS 1260 mg Metocel E10M 40 mg Carbopol 974P 20 mg Dye Etegak! Steep bake 4 mg Magnesium stearate 6.8 mg

-28007156

Bilayer tablet (sustained release and immediate release).

Immediate release layer

Composition II Composition III

Components Weight per tablet Weight per tablet Guaifenesin ES 421 mg 630.8 mg Microcrystalline Cellulose (Ανίοεί) 40 mg 353 mg Sodium Starch Glycolate (Exp1o1ab) 60 mg 90.1 mg Magnesium stearate 2 mg 3 mg

Slow Release

Composition II Composition III

Components Weight per tablet Weight per tablet Guaifenesin OS 842 mg 630.8 mg Metocel E1 OM 27 mg 40 mg Carbopol 974P 13.5 mg 20 mg Dye EtegaSh Sggeep Bake 3 mg 4 mg Magnesium stearate 4,5 mg 6.8 mg

The effects of each of the three slow-release tablets and the commercially available immediately-releasing composition, organidin ΝΚ (OguachsNp ΝΚ), were compared. The open-label study was conducted on 15 healthy volunteers with an average age of 31.67 ± 11.89 years, ranging from 20 to 51 years. Subjects weighed 162.00 ± 25.05 pounds (73.48 ± 11.36 kg), in the range of 123-212 pounds (55.79-96.16 kg). Each of the 15 subjects took 400 mg of the immediate-release composition every 4 hours for 12 hours in one day. The next day, 5 subjects took a slow release composition I, another 5 subjects took a slow release composition II, and another 5 subjects took a slow release composition III.

The results of the pharmacokinetic analysis of the parameters are shown below and are shown in FIG. 7.

Composition Tmax, (hour) Smake, (nanogram / ml) fox. ^ (hour-nanogram / ml) T1 / 2, (hour) Αυο, φ (hour-nanogram / ml) Average Organidin ΝΚ. (Ogdagpsip ΝΚ) 0.90 2609.40 8768.40 1.28 9082.78 Average Composition I 2,30 1631.40 5549.30 2.88 6044.93 Average Composition P 2,30 2415.40 7304.38 1.48 7509.78 Average Composition III 1.95 2938.00 8904.62 2.05 9161.03

Slow-release compositions II and III provide C _MAK s more comparable to the corresponding parameter. Immediate release composition and a higher AiS f _yn than non-layered, the sustained release composition I. both half cycles sustained releasing compositions II and III were less than half the period of a sustained release composition I. However, these bilayer tablets provide an improved plasma concentration of guaifenesin and more high total concentration over time.

Example 5

Dissolution processes were investigated in order to compare the dissolution profiles of composition I, composition II and composition III, prepared according to the procedure described in Example 4 above, and composition IV, batches of 200 mg, ΙΚ and 1000 mg, 8K bilayer tablets of the following composition.

-29007156

Immediate release layer

Composition GU

Components Weight per tablet Guaifenesin OS 211 mg Microcrystalline Cellulose (Ανίεεί) 118 mg Sodium Glycolate Starch (Exp1o1ab) 30 mg Magnesium stearate 1 mg

Slow Release

Composition GU

Components Weight per tablet Guaifenesin OS 1053 mg Metocel E10M 25 mg Carbopol 974P 12.5 mg Yeshega Dye 3.3 mg Magnesium stearate 5.7 mg

The summarized results, which are also shown in FIG. 8 are as follows:

Composition I (release, %) Composition II (release, %) Composition III (release, %) Composition GU (release, %) 1 hour 22 45 38 29th 2 hours 34 54 46 38 4 hour 43 65 56 48 6 hour fifty 70 61 53 8 hour 58 73 66 60 10 hour 62 78 70 66 12 hour 66 81 75 71

Composition I, not a two-layer tablet, showed the slowest release of guaifenesin. Composition II and composition III had the highest release rates and, accordingly, a shorter therapeutic effect ίη νίνο. Composition IV had a release rate faster than composition I, which did not include the immediate release composition, but was slower than composition II and composition III, both of which included more immediate release formulations than composition IV.

Example 6

The behavior of ίη νίνο of the two-layer tablets of composition IV prepared as described above in Example 5 was compared with the immediate-release composition [organidin ΝΚ (OgdashsNp п)]. An open-label cross-sectional 2-line study was conducted on 26 healthy volunteers aged an average of 31.31 ± 9.81 years, ranging from 19 to 50 years. Subjects weighed 166.77 ± 29.83 pounds (75.64 ± 13.53 kg). Subjects were divided into two experimental groups. Group 1 after nightly fasting took tablets of composition IV with 240 ml of water, every 12 hours for 5 days and one dose on the sixth day. Group 2 took 400 mg of organidine ΝΚ (OgdashLp ΝΚ) (2 tablets of 200 mg each) with 240 ml of water every 4 hours for 5 days and on the sixth day, one dose of 400 mg every 4 hours, for a total of 3 doses.

Blood samples were taken (5 ml with the addition of sodium heparin as an anticoagulant) on days 1, 4, 5, and 6 before dosing. On the first day after the initial dose, after 0.5; 0.75; one; 1.5; 2; 3; 4; 4,5; 4.75; 5; 5.5; 6; 7; 8; 8.5; 8.75; nine; 9.5; 10; 11 and 12 hours, additional blood samples were taken (5 ml each, with the addition of sodium heparin as an anticoagulant). On the sixth day after the initial dose through

-30007156

0.5; 0.75; one; 1.5; 2; 3; 4; 4,5; 4.75; 5; 5.5; 6; 7; 8; 8.5; 8.75; nine; 9.5; 10; eleven; 12; 14; At 16 and 24 hours, additional blood samples were taken (5 ml each, with the addition of sodium heparin as an anticoagulant).

The results of the analysis of pharmacokinetic parameters are given below.

The average test results - 11 twelve-hour intervals

Composition Tmax, (hour) With _m ax, (nanogram / ml) fox _M2 , (hour-nanogram / ml) T1 / 2, (hour) Ais ™ f, (hour-nanogram / ml) Average Organidyk (Oschatbt ΝΚ) 1,69 2463,20 8,381.93 0.78 8528.51 Average Composition IV 1.05 2111.38 7875.68 3.31 8,686.08

The results are shown in FIG. nine.

Stationary Testing

Composition Tmax, (hour) Smake, (nanogram / ml) ACOm (hour-nanogram / ml) T1 / 2, (hour) ΑΙΚ /, φ (hour-nanogram / ml)

Average Organidin. (Og§ap1s1t ΝΚ) 2.03 2278,20 7751.23 0.88 7962.14 Average Composition IV 0.86 2349.6 8202.47 3.61 9259.24

The results are shown in FIG. 10.

200/1000 mg bilayer tablets provide C _max and AiS _in f equivalent to the immediate-release mixture, a short T _max and a longer half-life of metabolism. Thus, a two-layer tablet with 200 mg of guaifenesin in the immediate-release composition and a slow-release composition with 1000 mg of guaifenesin give a tablet that forms a high plasma concentration of serum in a short period of time, however, it maintains an effective concentration of guaifenesin in the blood stream for a full 12 hours

Example 7

The relative bioaccumulation of two dosages of different strengths, with a modified release of guaifenesin, the compositions of the present invention, as well as the effect of food on the relative bioaccumulation of guaifenesin of the compositions of the present invention, was studied in normal, healthy male or female volunteers. Two batches of bilayer tablets of guaifenesin were prepared, one at 600 mg and the other at 120 0 mg.

Immediate release layer

600 mg tablet 1200 mg tablet

Components 200,000 tablets weight Weight per 100,000 tablets Guaifenesin ES 21.05 kg 21.05 kg Microcrystalline cellulose (Ανίοεί PH102) 11.75 kg 11.75 kg Sodium Starch Glycolate (Exp1o1ab) 3.00 kg 3.00 kg Magnesium stearate 0.1 kg 0.1 kg

-31 007156

Slow Release

600 mg tablet 1200 mg tablet

Components 200,000 tablets weight Weight per 100,000 tablets Guaifenesin OS 1005.27 kg 1005.27 kg Hydroxypropylmethyl cellulose Metocel E1 OM (Metocel E10M) 2,50 kg 2,50 kg Carbomer [Carbopol 974Р (Sagoro 1 974P)] 1.25 kg 1.25 kg Dye GO & SV1IEZH 1 A1shptit Bake Eue 0.33 kg 0.33 kg Magnesium stearate 0.57 kg 0.57 kg

The 1200 and 600 mg tablets were prepared the same, except for the number of tablets, depending on the amount of material used.

The behavior of ΐη νΐνο was compared: 600 mg tablets administered to volunteers in a fasting state (approximately 10 hours before dosing and approximately 4 hours after dosing), 1200 mg tablets administered to volunteers in a fasting state (approximately 10 hours before dosing and approximately 4 hours after dosing), and 1200 mg tablets administered to volunteers after eating very fatty foods (food was taken for 30 minutes during dosing). The open-label study was conducted on 27 healthy volunteers aged 18 to 55 years. 27 subjects were divided into three experimental groups: 9 took 600 mg tablets, 9 took 1200 mg tablets after an overnight fast, and 9 took tablets after eating very fatty foods for a period of 1 trial. After the completion of period 1, the volunteers underwent a cross-sectional study during period 2 (for example, so that 9 volunteers who received a 600 mg tablet for period 1 received a 1200 mg tablet under fasting conditions for period 2). After completing period 2, the volunteers in their third and final experimental group again underwent a cross-sectional study (i.e. 9 volunteers who received a 1200 mg tablet on a hunger strike for period 2 and a 600 mg tablet on a hunger strike for period 1 a 1200 mg tablet after eating very fatty foods for a period of 3). Each volunteer received one dose of the corresponding tablet and then was controlled for 16 hours.

Blood samples were taken approximately one hour before dosing and at certain intervals, for 16 hours after dosing (0.25; 0.5; 0.75; 1; 1.5; 2; 3; 4; 6; 8 ; 10; 12; 14 and 16 h).

The results of the pharmacokinetic analysis of the parameters are given below and in FIG. eleven.

Composition Tmax, (hour) Smake, (nanogram / ml) Lee% ₁₂ , (hour-nanogram / ml) T1 / 2, (hour) AIS ^ (hour-nanogram / ml) Average 600 mg, hungry 0.81 1074.26 3623.03 2,33 3676.23 Average 1200 mg, hungry 0.94 1948.62 7483.20 3.33 7912.61 Average 1200 mg, fed 2.18 1988.08 7424.20 0.91 7425.29

A 600 mg tablet showed a plasma profile that was approximately directly proportional to the plasma profile of the 1200 mg tablet. With a _max. 600 mg tablet, approximately 55% of the corresponding parameter of a 1200 mg tablet. ATGSo-p tablets in 600 mg accounted for approximately 48% of the corresponding parameter of the tablets in 1200 mg, and AIS _IN f tablets in 600 mg accounted for approximately 46% of the corresponding parameter of the tablet in 1200 mg. An improvement in the plasma concentration of guaifenesin and an increase in the total concentration over time, as well as half-cycle, occurred in concert with each other.

A 1200 mg tablet showed that the two-layer tablets of this invention greatly reduce the effect of food on bioaccumulation and plasma concentration of guaifenesin. With a _max 1200 mg tablet given after eating very fatty foods (a nutritional pill) was approximately 102% With a 1200 mg _max tablet taken under fasting conditions (a fasting pill). AiS ₀ . _n 1200 mg tablets with food was approximately 99% of the corresponding parameter tablets with starvation, and f _IN AiS

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A 1200 mg nutritional tablet was approximately 94% of the corresponding fasting tablet parameter.

Example 8

As an example of a combination of the drug composition, two batches of bilayer tablets of guaifenesin / dextromethorphan hydrobromide were prepared: ΐ) 600 mg / 30 mg dextromethorphan and i) 1200 mg / 60 mg. In a 30 mg tablet of dextromethorphan, 7.5 mg was within the immediate release layer, and 22.5 mg within the slow release layer. Accordingly, a 60 mg tablet of dextromethorphan comprises a double amount of dextromethorphan.

Slow Release

600 mg / 30 mg 1200 mg / 60 mg

Components 200,000 tablets weight (kg) Weight per 100,000 tablets (kg) Guaifenesin OS 101.00 kg 101.00 kg Dextromethorphan Hydrobromide 4.50 kg 4.50 kg Carbopol 974P, ΝΡ (Sagoro1 974P, ΝΡ) 1.50 kg 1.50 kg Microcrystalline cellulose [Metocel E10M (МеИюсе1 Е10М)] 5.00 5.00 Dye RO & CB1ieMo. one A1ittit Bake Eue 0.04 0.04 Magnesium stearate 1.00 1.00

Immediate release layer

600 mg / 30 mg 1200 mg / 60 mg

Components 200,000 tablets weight (kg) Weight per 100,000 tablets (kg) Guaifenesin OS 45.60 kg 45.60 kg Dextromethorphan Hydrobromide 3.60 kg 3.60 kg Sodium Glycolate Starch (Exp1o1a3) 3.60 kg 3.60 kg Microcrystalline cellulose [Avicel PH102 (Ανΐοεί PH102)] 40.32 40.32 Metocel E10M, ΕΙ8Ρ MeShose1E10M, i8R 2.40 2.40 Magnesium stearate 0.48 0.48

The summarized dissolution rate data for three different batches of 1200 mg guaifenesin / 60 mg dextromethorphan hydrobromide tablets are shown below and also shown in FIG. 12.

PB01-H30 (clinical batch),% release PB01-H43,% release PB01-H44,% release 1 hour 46 47 47 2 hours 59 60 61 6 hour 73 74 76 12 hour 86 87 89

The effect of ίη νΐνο 1200 mg of guaifenesin and 60 mg tablets was studied by measuring the plasma concentration of guaifenesin, dextromethorphan hydrobromide and dextrorphan metabolite. FIG.

-33 007156

13-15 illustrate the plasma concentration for each drug or metabolite in two compositions, in composition B and composition C for a period of 24 hours. Immediately after administration, after approximately one hour, the plasma concentration of guaifenesin reached peak values, and then more than after 24 hours, there was a gradual decrease in plasma concentration. Immediately after administration of guaifenesin, its plasma concentration never dropped below 200 ng / ml for 12 hours. After that, the plasma concentration of guaifenesin gradually decreased over the next 12 hours. The plasma peak concentration of dextromethorphan hydrobromide reached approximately 12 ng / ml in about 6 hours and this concentration was maintained for the next 19 hours

Presented in FIG. 13 compositions B and C show the same guaifenesin release profiles as standard compositions. As a standard composition for FIG. 13, Composition IV was selected from Example 5. Composition B included 77% by weight of guaifenesin, 3.8% by weight of dextromethorphan, 9.1% by weight of microcrystalline cellulose, 1.9% by weight of E10M metocel (Me1oye1 E10M) and 0, 9% carbopol® 974P (Sagoro1® 974P). Composition C included 76.5% by weight of guaifenesin, 3.8% by weight of dextromethorphan, 9.7% by weight of microcrystalline cellulose, 1.9% by weight of E10M metocel (Me1oye1 E10M) and 0.9% by weight of carbopol® 974P (Sagoro® 974P). Compositions B and C showed the same effect and had the same guaifenesin release profile as the standard composition. Accordingly, the combined compositions of the present invention do not affect the release of guaifenesin. In particular, in 12 hours, composition C released a larger dose of guaifenesin than the standard composition.

Compositions B and C of FIG. 13 were compared with a standard composition consisting of a slow-release dextromethorphan composition commercially available under the name Delsim (EeKut) and supplied by Zelltech (Ce1Yesy). The study was performed to determine the effect of the guaifenesin-dextromethorphan compositions of the present invention compared to the effect of the separately administered combined dextromethorphan compositions. Compositions B and C had longer dextromethorphan release profiles than the standard composition, as shown in FIG. 14. In addition, the combined compositions of this invention did not adversely affect the release profile of dextromethorphan.

Another method for controlling plasma concentrations of dextromethorphan is to measure plasma concentrations of the metabolite, dextrorphan. The plasma concentration of the dextrorphan metabolite of the standard composition and compositions B and C of FIG. 14 was plotted in FIG. 15. In general, the compositions showed the same concentrations of dextrorphan, and after 12 hours, composition C showed the highest concentration of dextrorphan. FIG. 15 shows that according to measurements of dextrorphan metabolite concentrations, the compositions of this invention containing guaifenesin do not inhibit the release process of dextromethorphan.

Example 9

Studies have been conducted regarding the bioaccumulation of a sustained release guaifenesin with dextromethorphan composition of the present invention, with the participation of normal, healthy male and / or female volunteers. A batch of 1200 mg guaifenesin and dextromethorphan bilayer tablets was prepared according to the composition described above in Example 8.

We studied the behavior of η νίνο 1200 mg tablets administered to volunteers under fasting conditions (approximately 10 hours before dosing and approximately 4 hours after dosing). The open-label study was conducted on 29 healthy volunteers, aged 18 to 55 years. 29 volunteers were divided into two experimental groups, half of which, under fasting conditions, took a 1200 mg tablet for the period of 1 trial. Each volunteer took one dose of the corresponding tablet and was then monitored for 16 hours.

Blood samples (7 ml each, with sodium heparin as an anticoagulant) were taken approximately 1 hour before dosing and at specific intervals up to 16 hours after dosing (0.25; 0.5; 0.75; 1; 1.5 ; 2; 3; 4; 6; 8; 10; 12; 14; and 16 h). The results of the pharmacokinetic parameters for analysis include guaifenesin T _max of 1.48 hr, C _max 2196 ng / mL, AIS _{0- 1} February 8702 hr-ng / mL, T _1/2 hr and 1.32 AIS _yn f ch 8732.5 ng / ml The results of the pharmacokinetic parameters for analysis of dextromethorphan include T _max 5.0 hours. With _max 5157 pg / ml, _{0. 1} February AIS 74209 hr-pg / mL, T _1/2 hr and 7.93 AIS _yn f 75016 hr-pg / ml

Example 10

In another example of a combination composition, two batches of a two-layer tablet of guaifenesin-pseudoephedrine hydrochloride, one per 600 mg and one per 1200 mg, were prepared in the following quantities.

- 34 007156

Slow Release

600 mg / 60 mg 1200 mg / 120 mg

Components Weight per 300,000 tablets (kg) Weight per 150,000 tablets (kg) Guaifenesin OS (95%) 157.90 157.89 Pseudoephedrine hydrochloride 18.0 18.00 Hydroxypropylmethyl cellulose [Metocel E10M (MeIyuse1 E10M)] 4,50 4,50 Carbopol 974Ρ, ΝΕ (Сагъоро1 974Р, ΝΕ) 2.25 2.25 Dye GO & S ΥεΙΙοχν, Νο. 6 Akishpish Bake (15-18%) 0.24 0.06 Magnesium stearate 1,50 1,50

Immediate release layer

600 mg / 60 mg 1200 mg / 120 mg

Components Weight per 300,000 tablets (kg) Weight per 150,000 tablets (kg) Guaifenesin OS (95%) 39,476 39,476 Microcrystalline cellulose [Avicel PH102 (Ανΐοβΐ PH102)] 22,028 22,028 Sodium Glycolate Starch 5,626 5,626 Magnesium Stearate, ΝΡ 0.188 0.188

The summarized dissolution rates for 1200 mg guaifenesin / 120 mg pseudoephedrine are shown below and are also shown in FIG. sixteen.

PB01-M65 (clinical batch),% release PB01-M68,% release PB01-M71, % release 1 hour 45 44 43 2 hours 60 59 58 6 hour 89 87 82 12 hour 97 98 96

The behavior of ΐη νίνο tablets of 1200 mg guaifenesin and 120 mg pseudoephedrine was studied by measuring the plasma concentration of guaifenesin and pseudoephedrine hydrochloride. Three batches of the composition 1200 mg guaifenesin / 120 mg pseudoephedrine hydrochloride were dissolved to determine the amount of pseudoephedrine hydrochloride released over time. Typically, the compositions contained 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride and were studied over a period of 12 hours. The released amount of pseudoephedrine hydrochloride was determined as a percentage of the weight of dissolved pseudoephedrine hydrochloride of the total weight of pseudoephedrine hydrochloride. After 1 hour, the amount of dissolved pseudoephedrine hydrochloride was approximately 43 to 45%. After 2 hours, approximately 58 to 60% was dissolved, after 6 hours, 82 to 89% was dissolved, and after 12 hours the amount of pseudoephedrine hydrochloride dissolved was approximately 96 to 97% by weight (see FIG. 16).

In order to investigate the effect of the additional drug on the guaifenesin release profile, three guaifenesin compositions were compared, two of which contained the additional drug, pseudoephedrine. FIG. 17-18 illustrate the plasma concentration for each drug (composition B and composition C) for a period of 24 hours. Immediately after administration of the drug, the plasma concentration of guaifenesin reaches peak values after about an hour, after which a gradual decrease in plasma concentration occurs within 24 hours. Not

-35 007156 slowly after administration of the drug for 12 hours, the plasma concentration of guaifenesin never fell below 200 ng / ml. After that, the plasma concentration of guaifenesin gradually decreased over the next 12 hours. The plasma concentration of pseudoephedrine hydrochloride peaked in about 6 hours and gradually decreased over the next 18 hours. Within 30 minutes after drug administration, the plasma concentration of pseudoephedrine hydrochloride never dropped below 50 ng / ml.

In FIG. 17 standard composition included composition IV from example 5 and a separate 12-hour composition Sudafed® (8ibaGeb®), available from ΡΓί / sr 1ps. 201 Taog Koab, Mogl P1a1I8, No. \ ν 1eggeu, 07950. The standard composition was compared with composition B and composition C of the present invention. Composition B included a delayed release composition containing 86% by weight of guaifenesin ES, 9.8% by weight of pseudoephedrine hydrochloride, 2.4% by weight of hydroxypropyl methylcellulose and 1.2% by weight of carbopol ® 974P (Cagoro 1 ® 974P) and an immediate release composition containing 52 wt.% guaifenesin OS and 39 wt.% microcrystalline cellulose. Composition C included 77% by weight of guaifenesin OS, 7.7% by weight of pseudoephedrine, 9% by weight of microcrystalline cellulose, 1.8% by weight of E10M metocel (Me11use1 E10M), and 0.9% by weight of carbopol ® 974P (Cagoro1 ® 974P). Compositions B and C showed similar behavior with separately administered compositions, thus demonstrating that the compositions of the present invention did not affect the release profile of pseudoephedrine.

In order to investigate the effect of the compositions of this invention on the release profile of pseudoephedrine, plasma concentrations of pseudoephedrine hydrochloride were studied. Plasma concentrations of pseudoephedrine for the compositions of FIG. 17 were plotted over a 24 hour period. As can be seen from FIG. 18, compositions B and C of FIG. 17 showed higher concentrations of pseudoephedrine than the standard composition. Thus, the combined compositions of this invention release pseudoephedrine in comparable or improved profiles than compositions containing pseudoephedrine alone.

Example 11

The relative bioaccumulation of delayed-release guaifenesin was studied in conjunction with the pseudoephedrine compositions of this invention in normal volunteers. A batch of 1200 mg guaifenesin and pseudoephedrine bilayer tablets was prepared according to the composition described above in Example 10.

We studied the behavior of ίη у1уо 1200 mg tablets administered to volunteers under fasting conditions (approximately 10 hours before dosing and approximately 4 hours after dosing). The open-label study was conducted on 29 healthy volunteers aged 18 to 55 years. 29 volunteers were divided into two experimental groups, half of which, under fasting conditions for the period of 1 trial, took a 1200 mg tablet. Each volunteer took one dose of the corresponding tablet and was then monitored for 16 hours.

Blood samples (7 ml each with sodium heparin as an anticoagulant) were taken approximately 1 hour before dosing and at specific intervals up to 16 hours after dosing (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 for analysis include guaifenesin T _max of 1.48 hr, C _max 2196 ng / mL, AIS _{0- 1} February 8702 hr-ng / ml, 1.32 T _1/2 hr and AIS 8732.5 h ^ f ng / ml. The results of the pharmacokinetic parameters analysis for pseudoephedrine include T _max 6 hours. C _max of 300 ng / ml, AIS _{0- 1} February 4201 hr-ng / ml, 5.98 T _1/2 hr and AISinf 4709 hr-ng / ml.

Example 12

In experiments with 15 healthy volunteers, slow-release formulations of guaifenesin and pseudoephedrine were compared with controlled-release commercially available formulations of guaifenesin and pseudoephedrine in a single dose, open-label, randomized, triple crossover study.

Subjects were randomized and were included in one of three experimental groups. Group A was given composition A, one product of a controlled release of commercially available 1,200 mg guaifenesin [mucinex (Mistech)] plus a product of a controlled release of commercially available 120 mg pseudoephedrine hydrochloride [Sudafed-12 h (8ibaGeb-12 Noig)] with 240 ml water after a night hunger strike. Group B received composition B (batch PB01-K61), an experimental controlled release tablet containing 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 ml of water after an overnight fast. Group C received composition C (batch SVOO-01A), another experimental controlled release tablet containing 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 ml of water after an overnight fast. There was at least a 7-day interval between doses.

The average age of the volunteers averaged 26.4 ± 10.57 years (mean ± standard deviation), in the age range of 18-50 years. Their growth was within 66.93 ± 4.37 inches (170 ± 11.1 cm), in the range of 60-74 inches (152.4 ± 188 cm). They weighed 160.87 ± 26.22 pounds (73 ± 11.89 kg), in the range of 118-222 pounds (53.52-100.7 kg). The group consisted of seven men (47%) and eight women (53%). Of the subjects, ten (67%) were of large physique, three (20%) of medium physique, and two (13%) of small physique. Thirteen volunteers (87%) were of Caucasian origin and two (13%) were many

- 36,007156 of national origin. Blood samples were taken (10 ml each with the addition of sodium heparin as an anticoagulant) before dosing, after dosing after 0.5; 0.75; one; 1.5; 2; 3; 4; 6; 8; 10; 12; 14; 16 and 24 hours

Subjects were given 1200 mg of guaifenesin in a standard guaifenesin (oiayepezt EC), C _max reached 1847 ng / mL in 0.78 hours and had AiS _yn f 7302 hr-ng / ml. Subjects were given 1200 mg of guaifenesin in the form of a composition in C _max reached 1784 ng / ml (103% of the standard) through h 0.82 (113% standard) and had AiS _yn f 7602 hr-ng / ml (109% of the standard). Subjects who were given 1200 mg of guaifenesin in the form of composition C reached C _{max of} 1154 ng / ml (65% of the standard) after 1.22 hours (179% of the standard) and had A&C _inf 7128 h-ng / ml (100% of the standard).

Subjects given pseudoephedrine hydrochloride with a dose of 120 mg in the form of sufedaf-12 h (8 ia £ 12-Noig) (standard) reached C _max 300 ng / ml (mean ± standard deviation) after 6 h and had AiSinf 4710 h-ng / ml Subjects who were given pseudoephedrine hydrochloride with a dose of 120 mg as composition B reached C _{max of} 285 ng / ml (99% of the standard) after 6 hours (101% of the standard) and had AIS _inf 4449 h-ng / ml (100% of the standard). Subjects who were given pseudoephedrine hydrochloride with a dose of 120 mg as composition C reached C _max 256 ng / ml (86% standard) after 8 hours (151% standard) and had AIS _inf 4444 h-ng / ml (97% standard).

Plasma concentrations of guaifenesin are depicted in FIG. 19. The obtained pharmacokinetic data are given in table. 1-4. The maximum plasma concentrations of guaifenesin after an oral dose of 1200 mg in the form of mucinex (Mistech) were 1847 ± 686.6 ng / ml and were achieved in 0.78 ± 0.28 hours. The area formed on the graph corresponds to the dependence: plasma concentration - time (AiSinf was 7302 ± 2866.4 h-ng / ml. The maximum plasma concentrations of guaifenesin after an oral dose of 1200 mg in the form of composition B were 1784 ± 549.9 ng / ml (102.93 ± 36.57% of the standard composition) and achieved after 0.82 ± 0.27 hour (112,78 ± 43,29% standard composition). _inf resulting Ais was 7602 ± 2492,8 hr-ng / ml (108,67 ± 23,93% standard compo The maximum plasma concentrations of guaifenesin after an oral dose of 1200 mg in the form of composition C were 1154 ± 523.3 ng / ml (64.56 ± 28.03% of the standard composition) and were achieved in 1.22 ± 0.45 h ( 178.9 ± 100.64% of the standard composition.) The obtained AIS _in f was 7128 ± 3166.0 h-ng / ml (99.81 ± 34.23% of the standard composition).

Table 1. Pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech) together with Sudafed 12 hours (8sh1a £ es1 12 Noig).

Subject C _M ax (nanogram / ml Tmax (hour) lioi, (hour-nanogram / ml) AIS ^, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 1847 0.78 7143 7302 3.60 188.98 Median 1530 0.75 5776 5863 3.21 204.68 Standard deviation 686.63 0.28 2793.41 2866.39 2.05 74.55 Standard error 183.51 0.08 746.57 766.08 0.55 19.92 % SU 37.18 35.92 39.11 39.26 56.94 39.45 Maximum 1847 0.78 7143 7302 3.60 188.98 Minimum 1530 0.75 5776 5863 3.21 204.68

Table 2. Pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of Composition B. Subject Smake (nanogram / ml Tmax (hour) AisSch (hour-nanogram / ml) fox% ₍₎ , (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 1784 0.82 7557 7602 1,59 172.56 Middle 1730 0.75 7297 7349 1.35 163.30 Standard deviation 549.90 0.27 2487.33 2492.75 0.59 49.49 Standard error 146.97 0,07 664.77 666.22 0.16 13.23 % SU 30.82 33.67 32.91 32.79 37.09 28.68 Maximum 1800 0.75 5818 5842 1.35 205.42 Minimum 1120 0.5 4952 4979 1.14 241.01

-37007156

Table 3. Pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of Composition C. Subject Smake (nanogram / ml Tmax (hour) lioi, (hour-nanogram / ml) Αυο «φ, (hour-nanogram / ml) Half period (hour) Clearance b / h

Middle 1154 132 6989 7128 2.40 202.57 Median 1050 1.00 6291 6314 2,38 190.05 Standard deviation 523.29 0.45 307833 3165.98 1.06 89.63 Standard error 139.86 0.12 822.69 846.14 0.28 23.96 % SU 45.35 37.14 44.04 44.41 44.30 4425 Maximum 612 0.75 3157 3205 125 374.38 Minimum 781 0.75 4902 4949 2.49 242.46

Table 4. The relationship between the pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of Composition B, and the corresponding parameters after the introduction of a standard composition, (%). Subject C _M ax (nanogram / ml Tmax (hour) fox, (hour-nanogram / ml) AiSzhf, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 102.93 112.78 11031 108.67 66.51 95.42 Median 90.59 100.00 102,28 100.45 50.76 99.55 Standard deviation 36.57 43.29 23.94 23.93 65.61 16.90 Standard error 9.77 11.57 6.40 6.40 17.53 4,52 % SU 35.53 38.38 21.70 22.02 98.64 17.72 Maximum 165.14 75 122.87 121.60 83.97 8234 Minimum 80 fifty 87.60 84.93 17.70 117.75

Plasma concentrations of pseudoephedrine are depicted in FIG. 20. The resulting pharmacokinetic data are given in table. 5-9. The maximum plasma concentrations of pseudoephedrine after an oral dose of 120 mg in the form of Sudafed-12 h (8iba £ eb 12 Noig) (standard) were 300.3 ± 91.44 ng / ml and were achieved in 6 ± 1.69 hours. The obtained AISinf was 4710 ± 1394.5 h-ng / ml. The maximum plasma concentrations of pseudoephedrine after an oral dose of 120 mg in the form of composition B were 285.3 ± 53.28 ng / ml (99.3 ± 20.39% of the standard composition) and were reached in 5.80 ± 2.40 h (101 , 11 ± 41.77% of the standard composition). The resulting AISinf was 4449 ± 1079.6 h-ng / ml (99.87 ± 26.40% of the standard composition). The maximum plasma concentrations of pseudoephedrine after an oral dose of 120 mg in the form of composition C were 256.4 ± 80.7 ng / ml (86.37 ± 14.38% of the standard composition) and were achieved in 8.27 ± 2.71 h (51 , 11 ± 73.25% of the standard composition). The obtained AIS _in f was 4444 ± 1212.1 h-ng / ml (96.78 ± 17.90% of the standard composition).

Table 5. Pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride in the form of Sudafed 12 hours (8iba £ eb 12 Noig) together with 1200 mg of guaifenesin in the form of Mucinex (Mistech). Subject Smake (nanogram / ml Tmax (hour) fox, (hour-nanogram / ml) AIS ^, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 30037 6.00 4201.62 4709.88 5.98 22.93 Median 287.00 6.00 4042.53 4601.31 5.19 21.37 Standard deviation 91.44 1,69 1182.92 1394.49 1.68 7.77 Standard error 24.44 0.45 316.15 372.69 0.45 2.08 % SU 30.45 28.17 28.15 29.61 28.01 33.87 Maximum 523 8 6518.45 7137.33 10.18 38.94 Minimum 183 4 2419.97 2524.37 4.29 13.77

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Table 6. Pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of Composition B. Subject Smake (nanogram / ml Tmax (hour) fox, (hour-nanogram / ml) fox ^., (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 285.33 5.80 4080.27 4448.85 5.40 23.41 Median 269.00 6.00 3985.05 4463.18 5.21 22.03 Standard deviation 53.28 2.40 946.92 1079.61 1.01 6.06 Standard error 14.24 0.64 253.07 288.54 0.27 1,62 % SU 18.67 41.32 23.21 24.27 18.64 25.88 Maximum 387 10 6003.14 6799.07 7.44 37.40 Minimum 215 2 2381.18 2628.19 3.85 14.46

Table 7. Pharmacokinetic parameters of pseudoephedrine after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of Composition C. Subject Smake (nanogram / ml Tmax (hour) fox, (hour-nanogram / ml) AiSnf, (hour-nanogram / ml) Half period (hour) Clearance B / hour Middle 256.40 8.27 4008.32 4444.09 5.39 23.85 Median 226.00 10.00 3888.93 4266.92 5.15 23.04 Standard deviation 80.71 2.71 1084.90 1212.13 1.10 7.16 Standard error 21.57 0.72 289.95 323.96 0.29 1.91 % SU 31.48 32.80 27.07 27.28 20.41 30,03 Maximum 448 10 6200.18 6756.67 8.66 40.05 Minimum 162 2 2360.01 2454.79 4.09 14.55

Table 8. The relationship between the pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of Composition B, and the corresponding parameters after administration of the standard composition, (%). Subject Smake (nanogram / ml Tmax (hour) AiSch, (hour-nanogram / ml) AIS ^, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 99.31 101.11 101.58 99.87 93.38 109.24 Middle 94.74 100.00 104.95 101.63 90.66 98.40 Standard deviation 20.39 41.77 24.96 26.40 17.54 40.60 Standard error 5.45 11.16 6.67 7.06 4.69 10.85 % SU 20.53 41.31 24.57 26.44 18.79 37.13 Maximum 140.40 200 139.07 144.72 120.84 234.43 Minimum 65.97 25 50.46 42.66 60.12 69.10

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Table 9. The relationship between the pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of Composition C, and the corresponding parameters after the introduction of a standard composition, (%). Subject Smake (nanogram / ml Tmax (hour) ASH ", (hour-nanogram / ml) ACSif, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 8637 151.11 96.79 96.78 93.98 107.04 Median 85.66 13333 98.75 99.37 96.77 100.63 Standard deviation 1438 7335 1434 17.90 21.06 22.01 Standard error 3.84 1938 3.80 4.78 5.63 5.88 % SU 16.65 48.48 14.71 18.49 22.41 20.56 Maximum 115.30 250 126.82 132.10 129.45 153.94 Minimum 62.60 fifty 75.98 64.96 5130 75.70

The data indicate that both compositions provide optimal bioaccumulation of guaifenesin (although composition B seems to be more consistent with the standard), and composition B provides optimal bioaccumulation of pseudoephedrine.

Example 13

We studied the dependence of bioaccumulation of a slow-release composition of guaifenesin at 1200 mg and pseudoephedrine hydrochloride at 120 mg on a dose of pseudoephedrine in normal volunteers compared to standard guaifenesin and pseudoephedrine hydrochloride according to an open-label, single-dose, randomized cross-section trial of 36 cross-sectional studies. The example also demonstrates dose proportionality of pseudoephedrine.

Subjects were randomized and were included in one of three experimental groups. Group 1 (treatment regimen A) was given a 1200 mg controlled release product of guaifenesin [mucinex (Mistech)] plus a 120 mg controlled release drug of commercially available pseudoephedrine hydrochloride [Sudafed®-12 h (8iba1eb®-12 Noig)] with 240 ml of water after an overnight fast (Standard). Group 2 (treatment regimen B) (PB01-M65A2) received an experimental, controlled release composition containing 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 ml of water after an overnight fast. Group 3 (treatment regimen C) (PB01-A12A) received an experimental, controlled release composition containing 600 mg of guaifenesin and 60 mg of pseudoephedrine with 240 ml of water after an overnight fast.

The average age of the volunteers averaged 23.4 ± 10.57 years (mean ± standard deviation), with an age range of 18-48 years. Their growth was in the range of 70.58 ± 3.08 inches (179.27 ± 7.82 cm) in the range of 64-75 inches (162.5-190.5 cm). They weighed 167.42 ± 26.14 pounds (73.67 ± 11.86 kg), with a range of 114-229 pounds (51.7-103.87 kg). Among the volunteers were twenty-four men (67%) and twelve women (33%). Of the subjects, sixteen (44%) were of large physique, thirteen (36%) of medium physique, and seven (19%) were of small physique. Thirty-two volunteers (89%) were of Caucasian descent, three (8%) were black and one (3%) was multinational. Blood samples were taken (10 ml, with the addition of sodium heparin as an anticoagulant) before dosing, after dosing after 0.5; 0.75; one; 1.5; 2; 3; 4; 6; 8; 10; 12; 14; 16 and 24 hours (the total amount of blood during the tests of guaifenesin and pseudoephedrine was 450 ml).

Subjects given 1200 mg of guaifenesin in the form of mucinex (Mistech) and 120 mg of pseudoephedrine hydrochloride in the form of Sudafed®-12 h (8iba £ eb®-12 Noig) (treatment regimen A, standard) reached Smake 1940 ng / ml at 0 , 77 h and had AIS _IN f 8061 h-ng / ml. Subjects given 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride as drug B (test) reached C _max 1813 ng / ml (98% of the standard) after 1.04 h (140% of the standard) and had an ACS of _{0 to} 8124 h-ng / ml (101% of standard). Subjects given 600 mg of guaifenesin and 60 mg of pseudoephedrine hydrochloride as drug C reached C _max 920 ng / ml (54% standard) after 0.99 h (179% standard) and had AiSinf 3565 h-ng / ml ( 46% of the standard).

Subjects given 120 mg of pseudoephedrine hydrochloride as Sudafed®-12 h (ZibaGeb®12 Noig) and 1200 mg of guaifenesin as mucinex (Mistech) (treatment regimen A, standard) reached Smake 250 ng / ml after 6 hours and had ACSinf 3847 h-ng / ml. Subjects given 120 mg of pseudoephedrine and 1200 mg of guaifenesin as an experimental composition (treatment regimen B, test) reached Smake 263 ng / ml (107% of the standard) after 5 hours (85% of the standard) and had ACSinf 3884 h-ng / ml (103% of standard). Subjects were given 60 mg of pseudoephedrine hydrochloride and 600 mg of guaifenesin in an experimental formulation (regimen C) reached C _ma kc 141 ng / ml (54% of the corresponding composition parameter B) in 5 h (100% of the corresponding composition parameter B), and had ACS _IN f 1968 h-ng / ml (50% of the corresponding parameter of composition B).

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Blood samples (10 ml each, with sodium heparin as an anticoagulant) were taken at the following intervals: before dosing, after dosing after 0.5; 0.75; one; 1.5; 2; 3; 4; 6; 8; 10; 12; 14; 16 and 24 hours. Bioequivalence was studied between the group taking the test composition (treatment regimen B - experimental composition of guaifenesin or pseudoephedrine hydrochloride) and the group taking the standard composition (treatment regimen A - standard composition of guaifenesin or pseudoephedrine hydrochloride). The relationship of dose-dependent responses between the group taking the test composition (treatment regimen B — experimental guaifenesin or pseudoephedrine hydrochloride) and the group taking the standard composition (treatment regimen C — standard composition guaifenesin or pseudoephedrine hydrochloride) was also investigated.

Plasma concentrations of guaifenesin are depicted in FIG. 21. The resulting pharmacokinetic data are given in table. 10-14. The maximum plasma concentrations of guaifenesin after an oral dose of 1200 mg in the form of mucinex (Mistech) and 120 mg of pseudoephedrine hydrochloride in the form of Sudafed 12 hours (8is1aGss112 Noit) were 1940 + 889 ng / ml and were achieved in 0.77 + 0.22 hours. formed on the graph corresponds to the dependence: plasma concentration - time (AISinf was 8061 + 3329 h-ng / ml. The maximum plasma concentrations of guaifenesin after an oral dose of 1200 mg in the form of drug B were 1813 + 900 ng / ml (98.1+ 35.8% of the standard composition) and were achieved in 1.04 + 0.49 h (140 + 65.3% of the standard The obtained AISinf was 8124 + 3677 h-ng / ml (101 + 19.3% of the standard composition) .The maximum plasma concentrations of guaifenesin after an oral dose of 600 mg in the form of drug C were 920 + 81 ng / ml (54, 3 + 20.2% of the standard composition) and were achieved in 0.99 + 0.46 h (116 + 78.7% of the standard composition). The obtained AISinf was 3565 + 1442 h-ng / ml (45.6 + 10.2 % of the standard composition).

Table 10. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Misseh) together with Sudafed 12 hours (ZibaGeb 12 Noig), (%). Subject Swah (nanogram / ml Tmax (hour) Aysoa, (hour-nanogram / ml) fox ^, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 1847 0.78 7143 7302 3.60 188.98 Median 1530 0.75 5776 5863 3.21 204.68 Standard deviation 686.63 028 2793.41 2866.39 2.05 74.55 Standard error 183.51 0.08 746.57 766.08 0.55 19.92 % SU 37.18 35.92 39.11 3926 56.94 39.45 Maximum 1847 0.78 7143 7302 3.60 188.98 Minimum 1530 0.75 5776 5863 3.21 204.68

Table 11. Pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition (Treatment regimen B, Test). Subject Smake (nanogram / ml Tmax (hour) AIssh (hour-nanogram / ml) ΑυΟ, φ, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 1813 1,04 8002 8124 221 175 Median 1530 0.75 7036 7083 1.99 169 Standard deviation 900 0.49 3677 3677 1.19 682 Standard error 154 0.08 631 631 0.20 11.7 % SU 49.6 46.9 45.9 45.3 53.9 38.9

Table 12. Pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 600 mg of guaifenesin and 60 mg of pseudoephedrine hydrochloride (Treatment regimen su.

Subject Swah (nanogram / ml Tmax (hour) Liov (hour ng / ml) Ais, ^, (hour ng / ml) Half period (hour) Clearance b / h Middle 920 0.99 3529 3565 1.76 192 Median 721 0.75 3078 3098 1.47 194 Standard deviation 481 0.46 1437 1442 0.92 66.5 Standard error 813 008 243 244 0.16 1,2 % SU 523 46, .0 40.7 40,4 52,4 34.5

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Table 13. The relationship between the pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of Composition B, and the corresponding parameters after administration of the standard composition (Treatment regimen A), (%). Subject C _M ax (nanogram / ml Tmax (hour) Aisch, (hour-nanogram / ml) fox ^, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 98.1 140 104 101 66,2 103 Median 96, .8 133 106 one hundred 53.1 99.5 Standard deviation 35.8 65.3 203 193 42.0 243 Standard error 6.14 OF 3.48 331 730 4.16 % SU 36, .5 46.5 193 19.1 63,4 23.5

Table 14. The relationship between the pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 600 mg of guaifenesin and 60 mg of pseudoephedrine hydrochloride (Treatment regimen C), and the corresponding parameters after the administration of Medication B, (%). Subject Smake (nanogram / ml Tmax (hour) AiSm, (hour-nanogram / ml) ASH.F, (hour-nanogram / ml) Half period (hour) Clearance B / hour Middle 543 116 45.9 45.6 97.0 114 Median 48.8 one hundred 43.9 44.0 86.1 114 Standard deviation 203 78.7 10.6 yuz 61.6 23,2 Standard error 3.47 13.50 1.82 1.75 1037 3.98 % SU 373 67.9 23.1 22.4 63.5 20.3

Plasma concentrations of pseudoephedrine are depicted in FIG. 22. The obtained pharmacokinetic data are given in table. 15-19. The maximum plasma concentrations of pseudoephedrine after an oral dose of 120 mg in the form of Sudafed® 12 h (8iba £ eb® 12 Noig) and 1200 mg of guaifenesin in the form of mucinex (Mistech) (treatment regimen A, standard) were 250 ± 53.4 ng / ml and were achieved in 6.29 ± 1.76 hours. The resulting AISinf was 3847 ± 910 h-ng / ml. The maximum plasma concentrations of pseudoephedrine after an oral dose of 120 mg as an experimental composition (treatment regimen B) were 263 ± 58.5 ng / ml (107 ± 18.9% of the standard composition) and were achieved in 5.11 ± 1.78 hours ( 85.2 ± 31.5% of the standard composition). The resulting AISinf was 3884 ± 911 h-ng / ml (103 ± 20.2% of the standard composition). The maximum plasma concentrations of pseudoephedrine after an oral dose of 60 mg in the form of an experimental composition (treatment regimen C) were 141 ± 30.3 ng / ml (53.5 ± 6.52% of composition B) and were achieved in 4.94 ± 1.60 h (99.5 ± 25.9% of composition B). The obtained AIS _IN f was 1968 ± 477 h-ng / ml (50.5 ± 8.77% of composition B).

Table 15. Pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride in the form of Sudafeda®-12 hours (8iba £ ec1®-12 Noig) and 1200 mg of guaifenesin in the form of Mucinex (Mistech) (Treatment regimen A). Subject Smake (nanogram / ml Tmax (hour) AShm, (hour nanogram / ml) ACS ^, (hourly nanogram / ml) Half period (hour) Clearance b / h Middle 250 6.29 3479 3847 5.75 27.1 Medium 252 6 3381 3652 5.42 26.9 Standard deviation 53,4 1.76 805 910 1,02 7.11 Standard error 9.16 0.30 138 156 0.18 132 % SU 213 28.0 233 23.7 17.8 263

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Table 16. Pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition (Treatment regimen wu Subject C _M ax (nanogram / ml Tmax (hour) AiSch, (hnanogram / ml) Αυο, ψ, (hour nanogram / ml) Half period (hour) Clearance b / h Middle 263 5.11 3591 3884 5.22 26.7 Medium 257 4.00 3507 3824 5.19 25.7 Standard deviation 58.5 1.78 824 911 0.89 6.23 Standard error 10.0 0.31 141 156 0.15 1,07

% SU I 223 I 34.8 I 23.0 | 23.5 | 16.9 | 23.3

Table 17. Pharmacokinetic parameters of pseudoephedrine after administration to normal volunteers of 60 mg of pseudoephedrine hydrochloride and 600 mg of guaifenesin in the form of an experimental composition (Treatment regimen C). Subject Smake (nanogram / ml Tmax (hour) Aioh, (hour ng / ml) AiSnf, (hour nanogram / ml) Half period (hour) Clearance B / hour Middle 141 4.94 1781 1968 5.57 26.5 Medium 134 4.00 1696 1855 5.38 26.5 Standard deviation 30.3 1,60 445 477 1,02 6.58 Standard error 5.12 0.27 75.1 80.6 0.17 1D1 % SU 21.5 32,4 25.0 24.2 18,4 24.9

Table 18. The relationship between the pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition (Treatment regimen B), and the corresponding parameters after administration of 120 mg of pseudoephedrine in the form of Sudafed®-12 hour (8i4a £ es1 ®-12 Noig) and 120 mg of guaifenesin in the form of Mucinex (Mistech) (Treatment regimen A), (%). Subject Smake (nanogram / ml Tmax (hour) lioi (hour ng / ml) AiSif, (hour nanogram / ml) Half period (hour) Clearance b / h Middle 107 85,2 105 103 92.1 101 Median 106 75.0 102 101 93.7 98.7 Standard deviation 18.9 31.5 19.39 20.16 15.19 22.03 Standard error 3.24 5.41 3.33 3.46 2.61 3.78 % SU 17.7 37.0 18,4 19.5 16.5 21.8

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Table 19. The relationship between the pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 60 mg of pseudoephedrine hydrochloride and 600 mg of guaifenesin in the form of an experimental composition (Treatment regimen C), and the corresponding parameters after administration of 120 mg of pseudoephedrine and 1200 mg of pseudoephedrine and 1200 mg of guaifenesin in the form of an experimental composition (Mode treatment B), (%). Subject Smake (nanogram / ml Tmax (hour) Aiom, (chapel- AiSchf, (chapel- Half period (hour) Clearance b / h

gram / ml) gram / ml) Middle 53.5 99.5 49.1 50,5 108 102 Median 52.6 one hundred 46.7 48.0 105 104 Standard deviation 6.52 25.9 7.80 8.77 17.4 162 Standard error 1.12 4.44 134 1,50 2.98 2.78 % SU 122 26.0 15.9 17.4 162 15.9

In conclusion, it should be noted that the experimental composition containing 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride is bioequivalent to standard compositions, administered in separate doses. In addition, the pharmacokinetics of guaifenesin and pseudoephedrine in the study range was linear.

Example 14

The effect of very fatty foods on the bioaccumulation of the combination composition has been investigated. The bioaccumulation of the composition of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride was compared with the bioavailability of a standard drug according to the open-label system as a single dose, randomized, by a bivariate cross-sectional study of 36 subjects.

Subjects were randomized and were included in one of two experimental groups. Group 1 was given 1200 mg of mucinex (Mistech) in the form of a product that slowed down the release of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of a Sudafed®-12 h preparation (8ija £ her®-12 Noig) with 240 ml of water 30 minutes after the start of taking very oily food (standard). Group 2 received an experimental composition containing 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 ml of water 30 minutes after the start of eating very fatty foods (test) (PB01-M65AZ).

Blood samples were taken (10 ml each with the addition of sodium heparin as an anticoagulant) before and after dosing after 0.5; 0.75; one; 1.5; 2; 3; 4; 6; 8; 10; 12; 14; 16 and 24 hours (the total amount of blood during the tests of guaifenesin and pseudoephedrine was 450 ml).

Subjects who took 1200 mg of guaifenesin as a mucinex preparation (Mistech) reached C _max 2207 h-ng / ml after 1.85 hours and had ACSinf 8067 h-ng / ml. Subjects who took 1200 mg of guaifenesin as an experimental composition (treatment regimen B) reached C _{max of} 1649 ng / ml (79% of the corresponding standard parameter) after 1.84 hours (118% of the corresponding standard parameter) and had A _& C _and nf 7663 hours ng / ml (93% of the corresponding standard parameter).

Subjects who took 120 mg of pseudoephedrine hydrochloride in the form of Sudafed®-12 h (8ija £ her®-12 Noig) reached C _max 268 ng / ml after 6.38 h and had AiSinf 3636 h-ng / ml. Subjects who took 120 mg of pseudoephedrine hydrochloride as an experimental composition (treatment regimen B) reached C _{max of} 274 ng / ml (103% of the corresponding standard parameter) after 4.80 hours (76.5% of the corresponding standard parameter) and had A&C _IN f 3528 h-ng / ml (96.5% of the corresponding parameter of the standard).

In addition, the bioequivalence data of the tested group were studied (treatment regimen B - 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride as an experimental composition) and standard group (treatment regimen A - standard composition of 1200 mg guaifenesin and 120 mg of pseudoephedrine hydrochloride).

Plasma concentrations of guaifenesin are depicted in FIG. 23. The obtained pharmacokinetic data are given in table. 20-22. The maximum plasma concentrations of guaifenesin after an oral dose of mucinex (Mistech) of 1200 mg were 2207 ± 952 ng / ml and reached in 1.85 ± 1.06 hours. The area formed on the graph corresponds to the dependence: plasma concentration - time (AISinf was 8067 ± 2663 h-ng / ml The maximum plasma concentrations of guaifenesin after an oral dose of the experimental composition of 1200 mg (treatment regimen B) were 1649 ± 690 ng / ml (79 ± 31.5% of the standard composition) and reached 1.84 ± 0.818 h (118 ± 68.8% of the standard composition). The obtained AISinf was 7663 ± 2864 h-ng / ml (93 ± 17.6% of the standard com position).

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Table 20. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech), together with 120 mg of pseudoephedrine hydrochloride in the form of Sudafed® 12 hours (8is1aGes1®-12 Noig), after n] eating very fatty foods (Mode: treatment A, Standard). Subject Smake (nanogram / ml T _M ax (hour) Aiom, (hour ng / ml) „Ο „φ, (hourly nanogram / ml) Half period (hour) Clearance b / h Middle 2207 1.85 8049 8067 1.22 168 Medium 2140 1,50 8160 8196 0.983 146 Standard deviation 952 1.06 2666 2663 0.621 64,4 Standard error 166 0.184 464 464 0.108 11.2 % SU 43,2 57.2 33.1 33.0 51.1 38.3

Table 21. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition, after ingestion of very fatty foods (Treatment regimen B, Test). Subject Smake (nanogram / ml Tmax (hour) Aioi, (hour ng / ml) Ais ^, (hour ng / ml) Half period (hour) Clearance b / h Middle 1649 1.84 7611 7663 1.40 181 Medium 1580 2.00 7474 7485 1,07 160 Standard deviation 690 0.818 2816 2864 0.793 77.6 Standard error 118 0.140 483 491 0.136 13.3 % SU 41.9 44,4 37.0 37,4 56.6 42.9

Table 22. The relationship between the pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition, and the corresponding parameters after administration of Medication A (Standard), after ingestion of very fatty foods, (%). Subject Smake (nanogram / ml Tmax (hour) AiSch, (hnanogram / ml) Ais ^, (hour ng / ml) Half period (hour) Clearance b / h Middle 79 118 93 93 135 109.9 Median 73 one hundred 91 91 99 109.8 Standard deviation 31.5 68.8 17.5 17.6 97.1 16.8 Standard error 5.51 12,2 3.09 3.12 17,2 2.96 % SU 39.8 58.3 18.8 18.9 72.0 153

Plasma concentrations of pseudoephedrine are depicted in FIG. 24. The obtained pharmacokinetic data are given in table. 23-25. Maximum plasma pseudoephedrine concentration after an oral dose of 120 mg sudafeda®-12 hr (8is1a1es1® Noig-12) was 268 ± 69.7 ng / ml achieved after 6.38 ± 1.26 hour. The resulting AiS _yn was 3636 ± f 940 h-ng / ml. The maximum plasma concentrations of pseudoephedrine after an oral dose of 120 mg of the experimental composition (treatment regimen B) were 274 ± 72.3 ng / ml (103 ± 10.3% of the standard composition) and were achieved in 4.80 ± 1.28 hours (76, 5 ± 23.1% of the standard composition). The obtained AIS _in f was 3528 ± 962 h-ng / ml (96.5 ± 11.7% of the standard composition).

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Table 23. Pharmacokinetic parameters of pseudoephedrine, after administration of 120 mg of pseudoephedrine hydrochloride in the form of Sudafeda®-12 hours (8i <1aGe4®-12 Noig) to normal volunteers, together with 1200 mg of Guaifenesin in the form of Mucinex (Mistech), after eating very fatty foods ( Treatment regimen A, Standard). Subject C _M ax (nanogram / ml Tmax (hour) AiSch, (hnanogram / ml) AIstsf, (hour nanogram / ml) Half period (hour) Clearance b / h Middle 268 6D8 3362 3636 538 28.8 Medium 249 6.00 3238 3545 4.97 27.7 Standard deviation 69.7 136 847 940 1,08 7.55 Standard error 12.1 0.319 147 164 0.188 131 % SU 26.03 19.67 25.18 25.86 20,42 26.19

Table 24. Pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride and 1200 mg of Guaifenesin in the form of an experimental composition, after taking very fatty foods (Treatment regimen B, Test). Subject Smake (nanogram / ml Tmax (hour) Au (%, (hnanogram / ml) fox ^, (hour ng / ml) Half period (hour) Clearance b / h Middle 274 4.80 3273 3528 536 30,0 Medium 268 4.00 3198 3448 531 28.5 Standard deviation 72.3 138 876 962 1,02 8.48 Standard error 123 0316 148 163 0.172 1.43 % SU 26,4 26.6 26.8 273 19,4 28.3

Table 25. The relationship between the pharmacokinetic parameters of pseudoephedrine, after the administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition, and the corresponding parameters after the administration of Medication A (Standard), after taking very greasy food (%) Subject Smake (nanogram / ml Tmax (hour) fox, (hour ng / ml) Ais „f, (hour ng / ml) Half period (hour) Clearance b / h Middle 103 76.5 96.5 96.5 101 105 Median 103 66.7 95.1 94.2 99.5 106 Standard deviation 103 23.1 10.6 11.7 17.9 12.6 Standard 1.82 4.09 1.88 2.06 3.17 233 mistake % SU 10.0 303 11.0 12.1 17.7 12.0

The absorption rate of guaifenesin from the experimental composition according to the value of C _{maK is} not bioequivalent to the absorption rate of the tested composition with a 95% confidence interval between 67.9 and 81.8% under conditions of eating very fatty foods. The degree of absorption of guaifenesin from the experimental tablet according to the value of ACSinf is equivalent to the degree of absorption of the test composition in the presence of very fatty foods.

In conclusion, it should be noted that the absorption rate of guaifenesin from the experimental composition is not bioequivalent to the absorption rate of the standard composition; at the same time, the degree of absorption of guaifenesin is bioequivalent to the degree of absorption of the standard composition in the presence of very fatty foods. The rate and extent of absorption of pseudoephedrine from the experimental composition is bioequivalent to the rate and extent of absorption of the standard composition in the presence of very fatty foods.

-46007156

Example 15

In experiments with 36 subjects, the combined composition of guaifenesin and pseudoephedrine was studied using an open-label, multiple-dose system, randomized, using a bivariate cross-sectional study of 36 subjects. Subjects were randomly assigned to one of two experimental groups. Group 1 took a 1200 mg controlled-release product of guaifenesin - mucinex (Mistech) plus a 120 mg pseudoephedrine controlled-release product of Sudafed®-12 h (ZibaGeb®-12 Noig) with 240 ml of water after overnight fasting and again, after 12 h, 11 doses (standard). Group 2 took an experimental, controlled-release composition, including 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride, with 240 ml of water after overnight fasting and again, after 12 hours, 11 doses (test) (PB01-M65).

Blood samples were taken (10 ml each with the addition of sodium heparin as an anticoagulant) on days 1, 4, 5, and 6 before noon dosing. 6 additional blood samples were also taken: per day (5 ml each, with the addition of sodium heparin as an anticoagulant), after 0.5; 0.75; one; 1.5; 2; 3; 4; 6; 8; 10; 12; 14; 16 and 24 hours after the last dose (the total amount of blood during the analysis of guaifenesin and pseudoephedrine was 380 ml).

Subjects who took 1200 mg of guaifenesin in the form of mucinex (Mistech) every 12 hours for a total of 11 doses reached the maximum steady-state plasma concentration of guaifenesin of 1960 ng / ml 0.81 hours after the last dose (120.81 hours after the first dose). The average AIC ₈₈ was 7209 h-ng / ml and the average C _min was 52 ng / ml. Those subjects who took 1200 mg of guaifenesin in the form of an experimental composition every 12 hours for a total of 11 doses reached the maximum steady-state plasma concentration of guaifenesin 1983 ng / ml (103% of the standard composition) within 0.96 hours after the last dose (after 120.96 hours after the first dose, 100% of the standard composition). The average value of AIC ₈₈ was 8183 h-ng / ml, (114% of the standard composition) and the average C _min value was 117 ng / ml.

In a stationary state, subjects who took 120 mg of pseudoephedrine hydrochloride in the form of Sudafed®-12 hours (ZibaGeb®-12 Noig) every 12 hours for a total of 11 doses reached the maximum steady-state plasma concentration of pseudoephedrine 361 ng / ml in 4.89 hours after the last doses (124.89 hours after the first dose). The mean value of AIC ₈₈ was 3528 h-ng / ml, and the mean C _min was 182 ng / ml. Those subjects who took 120 mg of pseudoephedrine hydrochloride as an experimental composition achieved a maximum steady-state plasma concentration of pseudoephedrine of 365 ng / ml (103% standard) 4.10 hours after the last dose (124.10 hours after the first dose, 99.4 % standard). The average value of AIC ₈₈ was 3550 h-ng / ml (102% of the standard), and the average C _min was 173 ng / ml.

Average plasma concentrations of guaifenesin are depicted in FIG. 25. The obtained pharmacokinetic data are given in table. 26-28. Subjects who received 12 mg of guaifenesin every 12 hours in the form of a standard preparation of mucinex (Mistech) with a total of 11 doses, reached a maximum plasma concentration of guaifenesin of 1960 ± 859 ng / ml (mean ± standard deviation) for 0.81 ± 0.305 h after the last dose (120.81 h after the first dose), and stationary A&S (A&S ₈₈ ) was 7209 ± 3746 h-ng / ml. Subjects who in a stationary state every 12 hours received 1200 mg of guaifenesin in the form of a tablet of the experimental composition with a total of 11 doses, under stationary conditions, reached a maximum plasma concentration of guaifenesin 1983 ± 1019 ng / ml [103 ± 29.6% of the standard preparation mucinex (Mistech) ] for 0.96 ± 0.645 hours after the last dose (120.96 hours after the first dose, 100 ± 0.494%). AIS ₈₈ was 8183 ± 5141 cng / ml (114 ± 27.0%).

Table 26. Stationary pharmacokinetic parameters of guaifenesin,

after administration to normal volunteers, 11 doses of 1200 mg of guaifenesin in the form of Mucinex (Mistech) and 120 mg of pseudoephedrine hydrochloride in the form of Sudafed®-12 hours (8iba £ eb®-12 Noig). (Treatment regimen A, Standard). Subject Aiszh, (hour-nanogram / ml) Cmin (nanogram / ml) Smake (nanogram / ml) Tknas (hour) Average (nanogram / ml) Middle 7209 52.0 1960 120.81 604 Medium 6554 28.3 1850 120.75 547 Standard deviation 3746 48.1 859 0,305 311 Standard error 633 8.13 145 0,052 52.6 % SU 52.0 92.5 43.8 0.253 51.5

-47 007156

Table 27. Stationary pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 11 doses of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition Treatment regimen B, (Test). Subject AIJ, (hour-nanogram / ml) Cmin (nanogram / ml) Smake (nanogram / ml) T "NS (hour) Average (nanogram / ml) Middle 8183 117 1983 120.96 686 Medium 6769 one hundred 1750 120.75 564 Standard deviation 5141 87.2 1019 0.645 431 Standard error 869 14.7 172 0.109 72.8 % SU 62.8 74.5 51,4 0.533 62.7

Table 28. The relationship between the stationary pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 11 doses of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition, and the corresponding parameters after administration of the Standard compositions, (%). Subject fox® Cmin Smake Tmayu Average Middle 114 550 103 one hundred 114 Medium 116 261 104 one hundred 113 Standard deviation 27.0 712 29.6 0.494 26,4 Standard error 4,57 120 5.01 0,084 4.46 % SU 23.7 129 28.6 0.494 23,2

Average plasma concentrations of pseudoephedrine are depicted in FIG. 26. The obtained pharmacokinetic data are given in table. 29-31. Subjects who, under stationary conditions, received 120 mg of pseudoephedrine hydrochloride every 12 hours in the form of Sudafed®-12 hours (8iba £ eb®-12 Noig) for a total of 11 doses, under stationary conditions reached a maximum plasma concentration of pseudoephedrine of 361 ± 77.7 ng / ml for 4.89 ± 2.14 hours after the last dose (124.89 hours after the first dose). Stationary AIS (AIS ₈₈ ) was 3528 ± 862 h-ng / ml. Subjects who, in a stationary state every 12 hours, received 120 mg of pseudoephedrine hydrochloride in the form of a tablet of an experimental composition with a total of 11 doses, under stationary conditions reached a maximum plasma concentration of pseudoephedrine of 365 ± 83.3 ng / ml [103 ± 21.4% of the standard drug Sudafed ®-12 hours (8iba £ eb®-12 Noig))] for 4.10 ± 1.85 hours after the last dose (124.10 hours after the first dose, 99.4 ± 2.09%). AIS ₈₈ was 3550 ± 898 cng / ml (102 ± 19.6%).

Table 29. The stationary pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 11 doses of 120 mg of pseudoephedrine hydrochloride in the form of Sudafed®-12 hours (8i4aGep®-12 Noig) and 1200 mg of guaifenesin in the form of Mucinex (Misseh). (Treatment regimen A, Standard). Subject lis (hour ng / ml) Cmin (nanogram / ml) Smake (nanogram / ml) Thomas (hour) Average (nanogram / ml) Middle 3528 182 361 124.89 294 Medium 3462 164 362 124.00 288 Standard deviation 862 66,4 77.7 2.14 71.9 Standard error 146 1i 13.1 0.361 W % SU 24.4 36.5 21.5 1.71 24.4

-48007156

Table 30. Stationary pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 11 doses of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition - Treatment regimen B, (Test). Subject fox®, (hour-nanogram / ml) C _min (nanogram / ml) Smake (nanogram / ml) TCiS (hour) Average (nanogram / ml) Middle 3550 173 365 124.10 296 Medium 3399 170 350 124.00 283 Standard deviation 898 55.2 83.3 1.85 74.8 Standard error 152 9.34 14.1 0.313 12.7 % SU 25.3 32,0 22.8 1.49 25.3

Table 31. The relationship between the stationary pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 11 doses of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition, and the corresponding parameters after administration of the Standard compositions, (%). Subject AiSzz, Cmin Smake Thomas Average Middle 102 one hundred 103 99,4 102 Medium 99.6 102 one hundred 99,2 one hundred Standard deviation 19.6 28.0 21,4 2.09 19.6 Standard error 331 4.73 3.62 0.354 331 % SU 19.1 27.9 20.8 2.11 19.1

In conclusion, it should be noted that under stationary conditions, the tablet of the experimental composition was bioequivalent to standard compositions. The experimental composition is bioequivalent to standard compositions in both respects, C _maK s and AIC ₈₈ for guaifenesin and pseudoephedrine hydrochloride.

Example 16

Another study was devoted to studying the possibilities of a combined composition, interacting with other drugs. The interaction potential for 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride was compared with the standard potential of the open-label system as a single dose, randomized, by tri-cross-sectional study of 36 subjects.

Subjects were randomized and were included in one of three experimental groups. Group A was given 1200 mg of a product of controlled release of commercially available guaifenesin [mucinex (Mistech)] with 240 ml of room temperature water after an overnight fast. Group B received 120 mg of the controlled release product of pseudoephedrine Sudafed®-12 h (8ida £ ed®-12 Noig) with 240 ml of room temperature water after an overnight fast. Group C received 1200 mg of the product guaifenesin, mucinex (Mistech), and 120 mg of pseudoephedrine hydrochloride, Sudafed®-12 h (8ida £ ed®-12 Noig) with 240 ml of room temperature water, after an overnight fast.

Blood samples were taken (10 ml each with the addition of sodium heparin as an anticoagulant) before and after dosing, after 0.5; 0.75; one; 1.5; 2; 3; 4; 6; 8; 10; 12; 14; 16 and 24 hours (the total amount of blood during the tests of guaifenesin and pseudoephedrine was 450 ml).

Subjects were given 1200 mg of guaifenesin in the form mutsineksa (Misteh) (regimen A, Standard), C _max reached 2009 ng / mL in 0.89 hours and had AiS _yn f 8138 hr-ng / ml. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) simultaneously with 120 mg of pseudoephedrine hydrochloride in the form of Sudafed®-12 h (8ida £ ed®-12 Noig) (treatment regimen C, test) reached C _max 1989 ng / ml (102% of the standard) after 0.84 hours (104% of the standard) and had AIS _in f 8052 h-ng / ml (100% of the standard).

Subjects given 120 mg of pseudoephedrine hydrochloride as Sudafed®-12 h (8ida £ ed®12 Noig) (treatment regimen B, standard) reached C _max 296 ng / ml after 6 h and had AIS _in f 4505 h-ng / ml Subjects who were given 120 mg of pseudoephedrine hydrochloride in the form of Sudafed®-12 h (8ida £ ed®-12 Noig) simultaneously with 1200 mg of guaifenesin in the form of mucinex (Mistech) (treatment regimen C, test) reached C _max 289 ng / ml (98% of the standard) after 6 hours (101% of the standard) and had AIS _in f 4396 h-ng / ml (98% of the standard).

-49007156

Plasma concentrations of guaifenesin are depicted in FIG. 27. The obtained pharmacokinetic data are given in table. 38-41. The maximum plasma concentrations of guaifenesin after an oral dose of mucinex (Mistech) of 1200 mg (treatment regimen A, standard) were 2009 ± 819.2 ng / ml and were achieved in 0.89 ± 0.42 hours. The area formed on the graph corresponds to the dependence: plasma concentration - time (AIS _in f was 8138 ± 3253 h-ng / ml. The maximum plasma concentrations of guaifenesin after an oral dose of 1200 mg in the form of mucinex (Mistech) together with 120 mg of pseudoephedrine hydrochloride (treatment regimen C, test) were 1989 ± 863 ng / ml (102.33 ± 31.40% of the standard composition) and were achieved in 0.84 ± 0.31 h (103.94 ± 35.38% st standard composition). The obtained AIS _in f was 8052 ± 3344 h-ng / ml (100.06 ± 18.09% of the standard composition).

Table 38. Pharmacokinetic parameters of guaifenesin after administration of 1200 mg of guaifenesin to normal volunteers (Treatment regimen A).

Subject Smake (nanogram / ml Tmax (hour) AisSch (hour-nanogram / ml) AiSnf, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 2009 0.89 7921 8138 4.00 172.13 Medium 1695 0.75 7063.8 7,284.17 2.82 164.87 Standard deviation 819.22 0.42 3196.53 325339 5.58 70.19 Standard error 138.47 0,07 54031 549.92 0.94 11.87 % SU 40.77 46.79 4035 39.98 139.48 40.78

Table 39. Pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin together with 120 mg of pseudoephedrine hydrochloride (Treatment regimen C). Subject Smake (nanogram / ml Tmax (hour) Aisch, (hour-nanogram / ml) AIsschf, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 1989 0.84 7923 8052 3.41 175.45 Medium 1770 0.75 6689 6745 3.33 177.93 Standard deviation 863.36 031 3337 3344 1.72 71.07 Standard error 145.93 0.05 564.04 565.25 0.29 12.01 % SU 43.41 36.37 42.12 41.53 50.56 40.51

Table 40. The relationship between the pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin together with 120 mg of pseudoephedrine hydrochloride, and the corresponding parameters after administration of one 1200 mg of guaifenesin, (%). Subject Smake (nanogram / ml Tmax (hour) fox, (hour-nanogram / ml) fox ^, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 102.33 103.94 100.87 100.06 128.38 103.47 Median 95.79 one hundred 103.14 101.71 107.41 98.32 Standard deviation 31.40 35.38 18.01 18.09 79.38 20.60 Standard error 5.31 5.98 3.05 3.06 13,42 3.48 % SU 30.69 34.04 17.86 18.08 61.83 19.91

Table 41. Pharmacokinetic parameters of pseudoephedrine after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride (Treatment regimen B).

Subject Smake (nanogram / ml Tmax (hour) fox, (hour-nanogram / ml) ΑϋΟ, ψ, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 295.8 6.17 4024 4505 6.05 23.66 Medium 297.5 6 3823 4430 5.81 22,20 Standard deviation 73.25 1.92 1047 1250 1.44 7.24 Standard error 12.38 0.32 177 211 0.24 1.22 % SU 24.76 31.13 26.02 27.75 23.83 30,60

-50007156

Plasma concentrations of pseudoephedrine are depicted in FIG. 28. The obtained pharmacokinetic data are given in table. 42-43. The maximum plasma concentrations of pseudoephedrine after an oral dose of Sudafeda-12 h (8is1aGss1 + -12 Noig) in 120 mg (treatment regimen B, standard) were 295.8 ± 73.25 ng / ml and were reached in 6.17 ± 1.92 h The resulting AISinf was 4505 + 1250 h-ng / ml. The maximum plasma concentrations of pseudoephedrine after an oral dose of Sudafeda®-12 h (Bsh1aGeb®-12 Noig) in 120 mg together with 1200 mg of guaifenesin in the form of kea mucin (Mistech) (treatment regimen C, test) were 289.3 + 77.61 ng / ml (98.41 + 12.77% of the standard composition) and were achieved in 5.75 + 1.54 hours (100.74 + 38.65% of the standard composition). The resulting AISinf was 4396 + 1347 h-ng / ml (98.40 + 15.24% of the standard composition).

Table 42. Pharmacokinetic parameters of pseudoephedrine after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride together with 1200 mg of guaifenesin (Treatment regimen C). Subject Smake (NZOgramm / ml Tmax (hour) AySya, (hour-nanogram / ml) ΑΓΚΑψ, (hour-nanogram / ml) Half period (hour) Clearance b / h Middle 289.33 5.75 3925 4396 6.04 24.30 Medium 286 6 3932 4247 5.63 23.16 Standard deviation 77.61 1,54 1089 1347 138 6.95 Standard error 13.12 0.26 184 228 0.23 1.17 % SU 26.82 26.74 27.75 30.65 22.79 28.60

Table 43. The relationship between the pharmacokinetic parameters of pseudoephedrine after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride together with 1200 mg of guaifenesin, and the corresponding parameters after administration of one 120 mg of pseudoephedrine, (%). Subject Smake (nanogram / ml Tmax (hour) AySya, (hour nanogram / ml) AiSnf (hourly nanogram / ml) Half period (hour) Clearance b / h Middle 98.41 100.74 98.22 98.40 103.30 103,99 Median 98.40 one hundred 96.90 97.91 97.46 102.14 Standard deviation 12.77 38.65 13.15 1534 30,44 15.96 Standard 2.16 6.53 2.22 2,58 5.14 2.70 mistake % SU 12.97 38.36 1339 15.49 29.47 1535

In conclusion, it should be noted that the pharmacokinetic parameters of guaifenesin and pseudoephedrine hydrochloride do not change in the presence or absence of each other.

Example 17

In another experiment, normal healthy volunteers again compared the effect of excess fat on bioaccumulation of a combination of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride, on the one hand, and a standard drug, on the other hand, according to an open-label system as a single dose, randomized, by bivariate cross-sectional study of 36 subjects.

Subjects were randomized and were included in one of two experimental groups. Both experimental groups did not eat at night. Experimental group A received an experimental composition containing 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 ml of water (standard). Experimental group B 30 minutes after the start of the intake of a very fat breakfast (test) received an experimental, controlled release composition containing 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 ml of water.

Blood samples were taken (10 ml each with the addition of sodium heparin as an anticoagulant) before and after dosing, after 0.5; 0.75; one; 1.5; 2; 3; 4; 6; 8; 10; 12; 14; 16 and 24 hours (the total amount of blood during the analysis of guaifenesin and pseudoephedrine was 300 ml). Subjects were given 1200 mg of guaifenesin and 120 mg pseudoephedrine hydrochloride in the form of an experimental composition after an overnight fast (regimen A, Standard), reach plasma concentration of guaifenesin C _ma kc 1857 ng / mL in 1.06 hours and had AISinf 8142 h- ng / ml Subjects given 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride as an experimental composition, after eating very fatty foods (treatment regimen B, test), reached C ,, _{1 | x} 1364 ng / ml (79.3% of the standard) after 2 06 h (238% of the standard) and had an ASGSinf of 7469 h-ng / ml (94.1% of the standard).

Subjects who were given 120 mg of pseudoephedrine hydrochloride as an experimental composition, after night fasting (treatment regimen A, standard), reached a plasma concentration of pseudoephedrine C ,, _{1 | x} 283 ng / ml in 4.6 hours and had an AISinf of 3746 h-ng / ml Subjects given 120 mg

-51 007156 pseudoephedrine hydrochloride in the form of experimental compositions, after eating very fatty foods (treatment regimen B, test), plasma concentrations of pseudoephedrine C _max 301 ng / ml (108% standard) were achieved after 5.77 h (137% standard) and had ACSinf 3660 h-ng / ml (99% of the standard).

Plasma concentrations of guaifenesin are depicted in FIG. 29. The obtained pharmacokinetic data are given in table. 44-46. The maximum plasma concentrations of guaifenesin after taking 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride, after night fasting were 1857 ± 838 ng / ml (mean ± standard deviation), and were achieved in 1.06 ± 0.582 hours. The area formed on the graph corresponds to the dependence : plasma concentration - time (ACS _yn f was 8142 ± 3500 chng / ml Maximum plasma concentration of guaifenesin after an oral dose of 1200 mg of guaifenesin and 120 mg pseudoephedrine hydrochloride in the form of an experimental composition, upon receiving high-fat meal (mode. sections B, test) were 1364 ± 691 ng / ml (79.3 ± 34.7% of the standard composition) and were achieved in 2.06 ± 1.16 h (238 ± 157% of the standard composition). The resulting ACSinf was 7469 ± 3217 cng / ml (94.1 ± 23.1% of the standard composition) .__________________________________________

Table 44. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition, after night fasting (Treatment regimen A, Standard). Subject Smake (nanogram / ml Tmax (hour) lyoch, (hour ng / ml) Αϋο, φ (hour ng / ml) Half period (hour) Clearance b / h Middle 1857 1.06 8091 8142 1.82 18.0 Medium 1830 0.750 8228 8244 1.68 14.6 Standard deviation 838 0.582 3501 3500 0.702 8.46 Standard error 144 0,100 600 600 0,120 1.45 % SU 45 55.0 43.3 43.0 38.6 47.0

Table 45. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition, after ingestion of very fatty foods (Treatment regimen B, Test). Subject Smake (nanogram / ml Tmax (hour) fisc, (hour ng / ml) Ais ^, (hour ng / ml) Half period (hour) Clearance B / hour Middle 1364 2.06 7403 7469 139 18.9 Medium 1190 2.00 6842 6857 1.12 17.5 Standard 691 1.16 3185 3217 0.833 7.80 deviation Standard error 119 ODO 546 552 0.143 134 % SU 50.7 56.6 43.0 43.1 60.0 413

Table 46. The relationship between the pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 120 mg of pseudoephedrine hydrochloride in the form of an experimental composition, after ingestion of very fatty foods (Treatment regimen B, Test), and the corresponding parameters after administration of the above experimental composition after nightly fasting (Treatment regimen A, Standard), (%). Subject Smake (nanogram / ml Tmax (hour) fisc, (hour ng / ml) Au% f, (hnanogram / ml) Half period (hour) Clearance b / h Middle 79.3 238 94.0 94.1 873 112 Median 71,4 200 89.7 89.6 68.1 112 Standard deviation 34.7 157 23,4 23.1 533 24.5 Standard error 6.04 27.4 4.07 4.02 937 4.26 % SU 43.8 66.1 24.8 24.6 61.1 21.9

-52007156

Plasma concentrations of pseudoephedrine are depicted in FIG. 45. The obtained pharmacokinetic data are given in table. 47-49. The maximum plasma concentrations of pseudoephedrine after taking 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition, after overnight fasting (treatment regimen A, standard) were 283 ± 79.6 ng / ml and were achieved in 4.60 ± 1.56 hours. The resulting AISinf was 3746 ± 997 h-ng / ml. The maximum plasma concentrations of pseudoephedrine after a dose of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition after eating very fatty foods (treatment regimen B, test) were 301 ± 80.4 ng / ml (108 ± 18.5% of the standard composition) and were achieved in 5.77 ± 1.78 hours (137 ± 61.9% of the standard composition). The resulting AISinf was 3660 ± 963 h-ng / ml (99.0 ± 20.1% of the standard composition).

Table 47. Pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition, after night fasting (Treatment regimen A, Standard). Subject Smake (nanogram / ml Tmax (hour) fox (hour nanogram / ml) Ais ^, (hour ng / ml) Half period (hour) Clearance b / h Middle 283 4.60 3477 3746 5.01 28,2 Medium 266 4.00 3374 3552 4.94 27.7 Standard deviation 79.6 1,56 884 997 1.06 8.03 Standard error 13.7 0.267 152 171 0.182 1.38 % SU 28,2 33.8 25,4 26.6 213 28.5

Table 48. Pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers of 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition, after ingestion of very fatty foods (Treatment regimen B, Test). Subject Smake (nanogram / ml T _ma x (hour) AiSch, (hnanogram / ml) fox ^ f, (hour nanogram / ml) Half period (hour) Clearance b / h Middle 301 5.77 3403 3660 4.64 28.8 Medium 292 6.00 3152 3455 4.45 28.5 Standard deviation 80,4 1.78 915 963 1.05 7.91 Standard error 13.8 0,306 157 165 0.180 1.36 % SU 26.7 30.9 26.9 26.3 22.6 27.5

Table 49. The relationship between the pharmacokinetic parameters of pseudoephedrine, after administration to normal volunteers 120 mg of pseudoephedrine hydrochloride and 1200 mg of guaifenesin in the form of an experimental composition, after ingestion of very fatty foods (Treatment regimen B, Test), and the corresponding parameters after administration of the above experimental composition after nightly fasting (Treatment regimen A, Standard), (%) Subject Smake (nanogram / ml Tmax (hour) fisc, (hour ng / ml) AYSinf, (hourly nanogram / ml) Half period (hour) Clearance b / h Middle 108 137 98.9 99.0 93.7 105 Median 109 133 96.9 95.9 88.4 104 Standard deviation 18.5 61.9 20.8 20.1 17.1 20,2 Standard error 3.22 10.8 3.62 3,50 2.97 3.52 % SU 17.1 45,2 21.0 20.3 18.2 193

The absorption rate of guaifenesin from the experimental composition according to the C _max value is not bioequivalent to the absorption rate of the test composition under very fatty foods. The degree of absorption of guaifenesin from the experimental tablet according to the value of APSynth is equivalent to the degree of absorption of the test composition in the presence of very fatty foods.

-53007156

The rate and extent of absorption of pseudoephedrine from the experimental composition was bioequivalent to the rate and extent of absorption of the standard composition in the presence of very fatty foods.

In conclusion, it should be noted that the absorption rate of guaifenesin from the experimental composition is not bioequivalent to the absorption rate of the standard composition; while the degree of absorption of guaifenesin is bioequivalent to the degree of absorption of the standard composition in the presence of very fatty foods. The rate and extent of absorption of pseudoephedrine from the experimental composition is bioequivalent to the rate and extent of absorption of the standard composition in the presence of very fatty foods.

Example 18

In another experiment, the relative bioaccumulation of guaifenesin and dextromethorphan was compared with normal volunteers: from a modified release experimental composition containing guaifenesin and dextromethorphan, on the one hand, and from standard medicinal products of guaifenesin and dextromethorphan, on the other hand, according to an open-label system, randomly, by a four-choice cross-sectional study of 36 subjects.

Subjects were randomized and were included in one of four experimental groups. Group 1 received a tablet of the experimental composition containing 1200 mg of controlled-release guaifenesin and 60 mg of controlled-release dextromethorphan hydrobromide (treatment regimen A) with 240 ml of water after an overnight fast. Group 2 received a standard controlled release tablet containing 1200 mg of guaifenesin [mucinex (Mistech), treatment regimen B] with 240 ml of water, after an overnight fast. Group 3 received 60 mg of dextromethorphan hydrobromide as a standard, immediate-release liquid composition, in 2 different dosage regimens [one half of the volunteers received 30 mg of dextromethorphan and after 6 hours the other 30 mg dose (treatment regimen C)], while the other half received 20 mg of dextromethorphan every 4 hours in three doses (treatment regimen с) with 240 ml of water, after an overnight fast. Group 4 received 30 mg of dextromethorphan hydrobromide in the form of a standard, immediate-release liquid composition, in 2 different dosage regimens [one half of the volunteers received 15 mg of dextromethorphan and after 6 hours the other 15 mg dose (treatment regimen E)], while the other half received 10 mg of dextromethorphan every 4 hours in three doses (treatment regimen P) with 240 ml of water, after an overnight fast. Those subjects who received 30 mg of dextromethorphan hydrobromide in one treatment period received 15 mg of dextromethorphan in another treatment period; likewise, those who received 20 mg of dextromethorphan in one treatment period received 10 mg of dextromethorphan in the subsequent treatment period. In this experiment, there was a 14-day interval between doses.

Blood samples were taken (7 ml, with the addition of sodium heparin as an anticoagulant) before and after dosing, after 0.5; 0.75; one; 1.5; 2; 3; 4; 5; 6; 7; 8; nine; 10; eleven; 12; 14; sixteen; 24; 36; 48; 72; and 96 h (the total amount of blood lost during the tests of guaifenesin and dextromethorphan was 644 ml).

Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) (standard, treatment regimen B) achieved an average C _{max of} 2145 ng / ml in 0.9 h and had an average AIC _{in of} 8953 cng / ml. Subjects who were given 1200 mg of guaifenesin in the form of an experimental composition also containing 60 mg of dextromethorphan hydrobromide (treatment regimen A) had an average value for guaifenesin C _{max of} 2176 ng / ml after 1.4 hours and an average AiSinf of 8766 h-ng / ml

Subjects given 60 mg of dextromethorphan hydrobromide together with 1200 mg of guaifenesin as an experimental composition (treatment regimen A) achieved an average value for dextromethorphan C _{max of} 4834 pg / ml in 5 hours and had an average AISinf of 68851 h-pg / ml. Subjects given 60 mg of dextromethorphan hydrobromide as a 30 mg dose every 6 hours (treatment regimen C) reached an average value for guaifenesin C _{max of} 4711 pg / ml after 8.3 hours and an average AISinf of 82655 chpg / ml. Subjects given 60 mg of dextromethorphan hydrobromide as a 20 mg dose every 4 hours (treatment regimen достиг) reached the average value for dextromethorphan C _max 3344 pg / ml over 7 hours and had an average AIS _in 44443 h-pg / ml. Subjects given 30 mg of dextromethorphan hydrobromide as a 15 mg dose every 6 hours (treatment regimen E) reached the average value for dextromethorphan C _max 2180 pg / ml after 8 hours and had an average AISinf of 40324 h-pg / ml. Subjects who were given 30 mg of dextromethorphan hydrobromide as a 10 mg dose every 4 hours (treatment regimen P) reached the average value for dextromethorphan C _max 1286 pg / ml after 7.7 hours and had an average AiSinf of 20114 h-pg / ml.

Plasma concentrations of guaifenesin are depicted in FIG. 33. The obtained pharmacokinetic data are given in table. 50-52. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) (treatment regimen B) achieved an average C _{max of} 2145 ± 997 ng / ml (mean ± standard deviation) for 0.91 ± 0.5 h and had an average AISinf 8953 ± 4272 h-ng / ml. Subjects who were given 1200 mg of guaifenesin in the form of an experimental composition containing also 60 mg of dextromethorphan hydrobromide (treatment regimen A) had an average value for guaifenesin C _{max of} 2176 ± 1320 ng / ml [101.36 ± 29.88% of mucinex ( Mistech)] after 1.44 ± 0.67 h [178.57 ± 82.70% of the drug

- 54 007156 mucinex (Mistech)] and the average value of AIS _in f 8761 ± 4755 h-ng / ml [99.57 ± 24.27% of the drug mucinex (Mistech)]. These data indicate that the presence of dextromethorphan does not affect the pharmacokinetics of guaifenesin ._______________________________________________________________________

Table 50. Pharmacokinetic parameters of guaifenesin after administration to normal volunteers of 1200 mg of guaifenesin together with 60 mg of dextromethorphan hydrobromide - Treatment regime A. Subject Smake (nanogram / ml Tmax (hour) Aisch, (hnanogram / ml) ASHIF, (hnanogram / ml) Half period (hour) Clearance b / h Middle 2176 1.44 8732 8761 131 179 Medium 1830 1,50 7579 7734 1,08 155 Standard deviation 1320 0.67 4761 4755 1.12 93.93 Standard error 237.15 0.12 855 854 0.20 16.87 % SU 60.67 46.88 54.52 54.27 85.67 52.59

Table 51. Pharmacokinetic parameters of guaifenesin after administration normal to volunteers of one 1200 mg of guaifenesin - Treatment regimen B. Subject Smake (nanogram / ml Tmax (hour) fisc, (hour ng / ml) Ais ^, (hour ng / ml) Half period (hour) Clearance b / h Middle 2145 0.91 8657 8953 4.79 171 Medium 1915 0.75 8346 8826 3.03 136 Standard deviation 997 0.50 4268 4272 4.85 94.28 Standard error 179 0.09 766 767 0.87 16.93 % SU 46.49 54.97 49.29 47.71 101.41 55.17

Table 51. The relationship between the pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin in the form of an experimental composition, together with 60 mg of dextromethorphan hydrobromide, and the corresponding parameters after administration of guaifenesin, (%). Subject Smake (nanogram / ml Tmax (hour) AiSch, (hnanogram / ml) fox ^, (hour ng / ml) Half period (hour) Clearance b / h Middle 101.36 178.57 102.78 99.57 47.71 106.07 Median 100.00 200.00 98.64 95.57 34.50 104.64 Standard deviation 29.88 82.70 23.27 24.27 39.04 25.35 Standard error 5.46 15.10 4.25 4.43 7.13 4.63 % SU 29.48 46.31 22.64 24.37 81.83 23.90

Plasma concentrations of dextromethorphan are depicted in FIG. 34. The obtained pharmacokinetic data are given in table. 53-61. Subjects given 60 mg of dextromethorphan hydrobromide as an experimental composition also containing 1200 mg of guaifenesin (treatment regimen A) achieved an average C _max value of 4834 ± 6182 pg / ml for dextromethorphan in 5.06 ± 0.93 h and had A&C _in f 68851 ± 112906 h-pg / ml. Subjects given 60 mg of dextromethorphan hydrobromide in the form of 30 mg doses every 6 hours (treatment regimen C) had, for dextromethorphan C, a _{maximum of} 4711 ± 6124 pg / ml (141.85 ± 82.73% of the experimental tablet, treatment regimen A) through 8.31 ± 1.58 h (62.07 ± 23.12% of treatment regimen A) and AiSinf 82655 ± 123509 h-PG / ml (108 ± 44.44% of treatment regimen A). Subjects given 60 mg of dextromethorphan hydrobromide as 20 mg doses every 4 hours (treatment regimen режим) achieved a mean C _{max of} 3130 ± 2355 pg / ml (100.31 ± 37.06% of the standard) for 7.01 for dextromethorphan ± 1.93 h (80.2 ± 22.83% of treatment regimen A) and had A&S _in f 44683 ± 37119 h-pg / ml (82.77 ± 22.93% of treatment regimen A). These data indicate that the tablet is not bioequivalent to any dosage regimen of dextromethorphan,

- 55 007156 however, is equivalent to the range created by these two dosage regimens. These data also indicate that the presence of guaifenesin does not affect the pharmacokinetics of dextromethorphan.

Subjects who were given 30 mg of dextromethorphan hydrobromide in the form of 15 mg doses every 6 hours (treatment regimen E) achieved a mean C _{max of} 2180 ± 2650 pg / ml (53.89 ± 17.62% of treatment regimen C) for dextromethorphan , 03 ± 2.52 h (96.08 ± 24.88% of treatment regimen C) and had A&S _in f 40324 ± 62644 h-pg / ml (51.73 ± 16.77% of treatment regimen C). Subjects who were given 30 mg of dextromethorphan hydrobromide in the form of 10 mg doses every 4 hours (treatment regimen P) had for _max dextromethorphan C 1286 ± 903 pg / ml (53.41 ± 12.82% of the treatment regimen через) after 7.73 ± 2.43 h (142.42 ± 67.86% of the treatment regimen ϋ) and A _& S _I nf 6945 ± 16158 h-PG / ml (54.32 ± 16.37% of the treatment regimen ϋ). These data show that the pharmacokinetics of dextromethorphan is linear in the studied range.

Table 53. Pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of an experimental composition containing 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin - Treatment regime A. Subject Smake (picogram / ml Tmax (hour) Aisch, (chaspicogram / ml) AisSchf, (chaspicogram / ml) Half period (hour) Clearance b / h Middle 4834 5.06 68189 68851 7.73 1697 Medium 2550 5.00 27821 28088 6.94 1088 Standard deviation 6182 0.929 112242 112906 1.78 1585 Standard error 1129 0.170 20493 20614 0.33 289 % SU 127.88 18.34 164.61 163.99 23.04 93.39

Table 54. Pharmacokinetic parameters of dextromethorphan, after administration to normal volunteers of 60 mg of dextromethorphan hydrobromide in the form of two 30 mg doses, each for 6 hours - Treatment regime C. Subject Smake (picogram / ml Tmax (hour) lysph (chaspicogram / ml) Αυο, φ, (chaspicogram / ml) Half period (hour) Clearance b / h Middle 4711 831 82279 82655 7.46 1291 Medium 1665 8.50 23483 23860 6.76 999 Standard deviation 6124 1,58 123157 123509 1.94 1078 Standard error 1581 0.41 31799 31890 0.50 278 % SU 129,99 19.01 149.68 149.43 25.97 83,45

Table 55. Pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 60 mg of dextromethorphan hydrobromide in the form of

three 20 mg doses, each in 4 hours - Treatment regimen ϋ. Subject Smake (picogram / ml Tmax (hour) lysph (chaspicogram / ml) АЫСщ |), (chaspicogram / ml) Half period (hour) Clearance b / h Middle 3130 7.01 44287 44683 7.04 1335 Medium 2720 6.00 26142 26321 6.60 1124 Standard deviation 2355 1.93 36759 37119 1,57 1098 Standard error 630 0.515 9824 9920 0.44 293 % SU 75.26 27,50 83.00 83.07 22.32 82.26

-56007156

Table 56. Pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 30 mg of dextromethorphan hydrobromide in the form of two 15 mg doses, each for 6 hours. Treatment regimen E. Subject Smake (picogram / ml Tmax (hour) Lyon, (chaspicogram / ml) AiStf, (chaspicogram / ml) Half period (hour) Clearance b / h Middle 2180 8.03 39746 40324 7.32 2940 Medium 1180 9.00 16061 16226 6.48 2735 Standard deviation 2650 2,52 61502 62644 228 2234 Standard error 684 0.65 15880 16175 0.59 577 % SU 121.59 31.37 154.74 155.35 31.13 75.98

Table 57. Pharmacokinetic parameters of dextromethorphan, after administration to normal volunteers 30 mg of dextromethorphan hydrobromide in the form of three 10 mg doses, each for 4 hours - Treatment regimen E. Subject Smake (picogram / ml Tmax (hour) Lyon, (chaspicogram / ml) Ais ^ f, (chaspicogram / ml) Half period (hour) Ground clearance E / hour Middle 1286 7.73 19833 20114 7.44 3894 Medium 795 6.00 12940 13170 6.95 2860 Standard deviation 903 2.43 16162 16158 2.02 3274 Standard error 241 0.650 4319 4318 0.54 875 % SU 70.19 31.47 81.49 80.33 27.18 84.09

Table 58. The relationship between the pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 60 mg of dextromethorphan hydrobromide in the form of treatment regimen A, and the corresponding parameters with the introduction of the same drug in the form of two

30 mg doses each for 6 hours (Treatment regimen C),%. Subject Smake Tmax lyoi Ais ^ nf, Half period Clearance Middle 141.85 62.07 106.81 108.00 107.71 122.40 Median 121.79 59.03 95.92 96.02 108.89 107.97 Standard deviation 82.73 23.12 43.92 44,44 9.65 60.31 Standard error 21.36 5.97 11.34 11.47 2.49 15,57 % SU 58.32 37.25 41.12 41.15 8.96 49.28

Table 59. The relationship between the pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 60 mg of dextromethorphan hydrobromide in the form of Treatment regimen A, and the corresponding parameters after administration of the same drug in the form of three 20 mg doses, each for 4 hours (Treatment regimen ϋ),%. Subject Smake Tmax lyoi AiSmnf, Half period Clearance Middle 100.31 80.02 83.01 82.77 107.26 164.60 Median 94.35 83.33 77.49 77.84 101.62 158.65 Standard deviation 37.06 22.83 23.39 22.93 16.71 88.09 Standard error 10.70 6.59 6.75 6.62 4.82 25.43 % SU 36.94 28.53 28.18 27.71 15,57 53.52

-57007156

Table 60. The relationship between the pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 30 mg of dextromethorphan hydrobromide in two 15 mg doses, each for 6 hours (Treatment regimen E), and the corresponding parameters after administration of 60 mg of dextromethorphan hydrobromide in two 30 mg doses, each for 6 hours (Treatment regimen C),%. Subject Smake Tmax fox AiSnf, Half period Clearance Middle 53.89 96.08 51.35 51.73 98.33 278.94 Median 57.20 100.00 50.70 50.64 103.29 214.90 Standard deviation 17.62 24.88 16.64 16.77 14.88 172.08 Standard error 4,55 6.42 4.30 4.33 3.84 44,43 % SU 32.70 25.89 32,40 32,42 15.14 61.69

Table 61. The relationship between the pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 30 mg of dextromethorphan hydrobromide in three 10 mg doses, each for 4 hours (Treatment regimen E), and the corresponding parameters after administration of 60 mg of dextromethorphan hydrobromide in three 20 mg doses, each for 4 hours (Treatment regimen ϋ),%. Subject Smake Tmax Lio " AiSchf, Half period Clearance

Middle 53.41 142.42 54.28 54.32 103.46 313.85 Median 56.73 166.67 52.75 52.23 89.13 255.28 Standard deviation 12.82 67.86 16.26 16.37 35.81 143.22 Standard error 6.41 33.93 8.13 8.19 17.91 71.61 % SU 24.00 47.65 29.95 30.14 34.62 45.63

In conclusion, it should be noted that the presence of another component has no effect on the pharmacokinetics of guaifenesin and dextromethorphan, and the pharmacokinetics of dextromethorphan is linear in the studied range.

Example 19

In another experiment with normal volunteers, the relative bioaccumulation of guaifenesin and dextromethorphan was compared: from a modified release experimental composition containing guaifenesin and dextromethorphan, on the one hand, and from standard guaifenesin and dextromethorphan, on the other, according to an open-label system as a separate dose, randomized , by a three-way cross-sectional study of 36 subjects.

Subjects were randomized and were included in one of three experimental groups. Group 1 received a controlled-release product of guaifenesin in the form of mucinex (Mistech) for 1200 mg plus 60 mg of dextromethorphan hydrobromide (administered as 30 mg doses every 6 hours) with 240 ml of water, after night fasting (standard). Group 2 received a controlled-release product of guaifenesin in the form of mucinex (Mistech) for 1200 mg plus 60 mg of dextromethorphan hydrobromide (administered as 20 mg doses every 4 hours) with 240 ml of water, after an overnight fast (standard). Group 3 received an experimental, controlled-release tablet containing 1200 mg of 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 interval between doses.

Blood samples were taken (7 ml each with the addition of sodium heparin as an anticoagulant) before and after dosing, after 0.5; 0.75; one; 1.5; 2; 3; 4; 4,5; 4.75; 5; 5.5; 6; 6.5; 6.75; 7; 7.5; 8; nine; 10; eleven; 12; 14; sixteen; 24; 36; 48; 72 and 96 hours (the total amount of blood lost during the analysis of guaifenesin and dextromethorphan was 609 ml). Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in two 30 mg doses after 6 hours each (treatment regimen A, standard) reached a plasma concentration of guaifenesin on average C _{max of} 1743 ng / ml via 1.25 h and had A&C _in f 7836 h-ng / ml. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in three 20 mg doses, after 4 hours each (treatment regimen B, standard), reached a plasma concentration of guaifenesin on average С _M ax 1783 ng / ml after 1.27 h and had AiS _in f 7616 h-ng / ml. Subjects given 1200 mg of guaifenesin as an experimental composition, as well as 60 mg of dextromethorphan hydrobromide (regimen

Treatment -58 007 156 C test), the plasma concentration of guaifenesin attained in the average C _max 1710 ng / mL in 1.55 hours and had AiS _yn f 7102 hr-ng / ml.

Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in the form of 30 mg of Vika's cough medicine 44 (Ukk'z Rogti1a 44 Co1sh11 MesNste) and after another 6 hours another 30 mg dose of dextromethorphan hydrobromide (treatment regimen A, standard), the plasma concentration for dextromethorphan reached an average of C _max 7946 pg / ml for 8.32 hours and had AiSinf 294267 h-pg / ml. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in the form of 20 mg of Vika's cough medicine 44 (U1sk'8 Rogt1a 44 Co1shch11 Mesiste), after 4 hours a second 20 mg dose and after another 4 more h - a third dose of 20 mg dextromethorphan hydrobromide (regimen B, standard), reaching values for plasma concentrations of dextromethorphan average C _max 8598 pg / ml after 8,90 h and had AiS _yn f 339447 hr-pg / ml. Subjects were given 1200 mg of guaifenesin in conjunction with 60 mg of dextromethorphan hydrobromide in an experimental formulation (regimen C test), the values of plasma concentrations achieved for dextromethorphan average C _max 7483 pg / ml after 6,30 h and had AiS _yn f 316592 h-pg / ml.

P1 plasma concentrations of guaifenesin are depicted in FIG. 35. The obtained pharmacokinetic data are given in table. 62-64. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in two 30 mg doses, after 6 hours each (treatment regimen A, standard), reached the plasma concentration for guaifenesin in the average Smak 1743 ± 903 ng / ml (mean ± standard deviation) for 1.25 ± 0.660 h and had A&S _in f 7836 ± 3616 cng / ml. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in three 20 mg doses after 4 hours each (treatment regimen B, standard) achieved a plasma concentration of guaifenesin on average C _{max of} 1783 ± 808 ng / ml for 1.27 ± 0.833 h and had A&S _in f 7616 ± 3398 h-ng / ml. Subjects who were given 1200 mg of guaifenesin in the form of an experimental composition together with 60 mg of dextromethorphan hydrobromide (treatment regimen C, test) achieved a plasma concentration for guaifenesin on average C _{max of} 1710 ± 807 ng / ml for 1.55 ± 0.789 hours and had AIS _in f 7102 ± 2807 h-ng / ml.

Table 62. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech), together with 60 mg of dextromethorphan hydrobromide in the form of 30 mg of Vika's Cough Medication 44 (Uglsk Rogty1a 44 Sojes MesNste), and later 6 hours, another 30 mg dose of dextromethorphan hydrobromide (Treatment regimen A, Standard) Subject Smake (nanogram / ml Tmax (hour) fisc, (hour ng / ml) Αυο, φ, (hour nanogram / ml) Half period (hour) Clearance b / h Middle 1743 1.25 7730 7836 2.60 192 Medium 1545 1.00 6854 6956 2.27 173 Standard deviation 903 0.660 3578 3616 1.37 109 Standard error 147 0.107 580 587 0.221 17.7 % SU 51.8 52.7 46.3 46.1 52,4 57.0

Table 63. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech), together with 60 mg of dextromethorphan hydrobromide in the form of 20 mg of Vika Cough Medicine 44 (Uyk'z Roppi1a 44 Soi§es Mesiste), after 4 hours, the second 20 mg dose, and after 4 hours, the third 20 mg dose of dextromethorphan hydrobromide (Treatment regimen B, Standard), Subject Smake (nanogram / ml Tmax (hour) lioi (hour ng / ml) AiSnf, (hour nanogram / ml) Half period (hour) Clearance b / h Middle 1783 1.27 7477 7616 3.19 191 Medium 1615 1.00 6948 7268 2.77 165 Standard deviation 808 0.833 3369 3398 1.83 90.1 Standard error 137 0.141 570 574 0,307 15,2 % SU 45.3 65.5 45.1 44.6 56.9 47.2

- 59007156

Table 64. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin, together with 60 mg of dextromethorphan hydrobromide in the form of an experimental composition (Treatment regimen C, Test).

Subject Smake (nanogram / ml Tmax (hour) Aisf, (hour nanogram / ml) fox ^ f, (hour nanogram / ml) Half period (hour) Clearance b / h Middle 1710 1.55 7082 7102 1.24 201 Medium 1525 1,50 6847 6899 1.05 174 Standard deviation 807 0.789 2805 2807 0,501 one hundred Standard error 141 0.137 488 489 0,087 17.4 % SU 47.2 51.0 39.6 39.5 40.5 49.8

Plasma concentrations of dextromethorphan are depicted in FIG. 36. The obtained pharmacokinetic data are given in table. 65-67. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in the form of 30 mg of Vika's cough medicine 44 (U1sk'§ koptyk 44 Soidk Mesiste), and after 6 hours another 30 mg dose of dextromethorphan hydrobromide (regimen treatments a, standard), reaching values for plasma concentrations of dextromethorphan average C _max 12386 ± 7946 pg / mL at 8.32 ± 2.88 hours and had AiS _yn f 294267 ± 724235 hr-pg / ml. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in the form of 20 mg of Vika's cough medicine 44 (U1sk'Gegi1a 44 Soid Mesiste), after 4 second 20 mg and after another 4h-third 20 mg dose of dextromethorphan hydrobromide (regimen B, standard), reaching values for plasma concentrations of dextromethorphan average C _max 13559 ± 8598 pg / mL at 8.90 ± 3.62 hours and had AiS _yn f 339447 ± 850232 hr-ng / ml Subjects given 60 mg of dextromethorphan hydrobromide together with 1200 mg of guaifenesin as an experimental composition (treatment regimen C, test) achieved a plasma concentration of dextromethorphan on average C _{max of} 7483 ± 12332 pg / ml in 6.30 ± 2.64 h and had AIS _in f 316592 ± 796975 h-pg / ml.

Table 65. Pharmacokinetic parameters of dextromethorphan, after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech), together with 60 mg of dextromethorphan hydrobromide in the form of 30 mg of Vika Cough Medicine 44 (U1sk'z Gogti1a 44 Sidk MesNste), and after 6 hours , another 30 mg dose of dextromethorphan hydrobromide (Treatment regimen A, Standard)

Subject Smake (picogram / ml Tmax (hour) Aisf, (chaspico- AiSchf, (chaspico- Half period (hour) Clearance b / h gram / ml) gram / ml) Middle 7946 8.32 248123 294267 10.9 2044 Medium 2375 8.00 31290 31544 7.57 1394 Standard deviation 12386 2.88 575122 724235 9.42 2153 Standard error 2009 0.468 93297 1 17486 1,53 349 % SU 156 34.7 232 246 86.2 105

-60007156

Table 66. Pharmacokinetic parameters of dextromethorphan, after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech), together with 60 mg of dextromethorphan hydrobromide in the form of 20 mg of Vic's Cough Medicine 44 (Uyk'z Rogtya 44 Soi ^ MesNste), after 4 hours, the second 20 mg dose, and after 4 hours, the third 20 mg dose of dextromethorphan hydrobromide (Treatment regimen B, Standard), Subject Smake (picogram / ml Tmax (hour) lyomas, (chaspicogram / ml) AySdaf, (chaspicogram / ml) Half period (hour) Ground clearance G / hour Middle 8598 8.90 271074 339447 11.3 1920 Medium 2470 7.75 31698 31978 7.11 1374 Standard deviation 13559 3.62 641451 850232 11,4 1655 Standard error 2292 0.612 108425 143715 1.93 280 % SU 158 40.7 237 250 101 86.2

Table 67. Pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide in the form of an experimental composition (Treatment regimen C, Test). Subject Smake (picogram / ml Tmax (hour) leaf, (chaspicogram / ml) Ais ^, (hour PICgram / ml) Half period (hour) Clearance B / hour Middle 7483 6.30 253196 316592 12.6 2756 Medium 2550 5.50 24730 24981 8.64 1760 Standard deviation 12332 2.64 604557 796975 11.5 3530 Standard error 2115 0.453 105240 138735 2.00 614 % SU 165 42.00 239 252 91.7 128

Dextromethorphan hydrobromide is widely known as a drug with a very variable effect, and therefore the width of its confidence interval is considered bioequivalent to 70-143%, and not the classic 80-125%. In conclusion, it should be noted that in an experimental guaifenesin tablets clearly bioequivalent to the standard, mutsineksu (Misteh), the parameters C _poppy, AIS ₀ or -1 AiS _yn f, since all 90% confidence intervals are within 80-125 % Dextromethorphan hydrobromide as an experimental tablets, the parameters C _poppy, AIS ₀₄ or AiS _yn f, can be considered bioequivalent to 30 mg of dextromethorphan hydrobromide every 6 hours, and 20 mg every 4 hours, as the 90% confidence intervals are -th within 70- 143%.

Example 20

In another experiment with normal volunteers, the relative bioaccumulation of guaifenesin and dextromethorphan was compared: from a modified release experimental composition containing guaifenesin and dextromethorphan, after eating very fatty foods, on the one hand, and after night fasting, on the other, according to the open-label system, as a single dose, randomized, by a bivariate cross-sectional study of 36 subjects.

Subjects were randomized and were included in one of two experimental groups. Experimental group A received 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide with 240 ml of water, after an overnight fast (standard). Experimental group B received 1200 mg of guaifenesin and an experimental tablet of dextromethorphan hydrobromide with 240 ml of water for 30 minutes after the start of eating very fatty foods (test). In this experiment, there was a 14-day interval between doses.

Blood samples were taken (7 ml, with the addition of sodium heparin as an anticoagulant) before and after dosing, after 0.5; 0.75; one; 1.5; 2; 3; 4; 5; 6; 8; 10; 12; 14; sixteen; 24; 36; 48; 72; and 96 h (the total amount of blood lost during the analysis of guaifenesin and dextromethorphan will be 280 ml). Subjects given 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide as an experimental composition after an overnight fast (treatment regimen A, standard) reached an average of C _max 2030 ng / ml after 1.61 h and had A&C _in f 8128 h-ng / ml Subjects given 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide after eating very fatty foods (treatment regimen B, test) achieved an average of C _{max of} 1825 ng / ml (98.0% of treatment regimen A) in 2.93 hours (248 % of treatment regimen A) and had AiSinf 7093 h-ng / ml (92.9% of treatment regimen A).

-61 007156

Subjects given 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin as an experimental composition after overnight fasting (treatment regimen A, standard) achieved a plasma concentration for dextromethorphan of an average C _{max of 10772} pg / ml in 6.23 h and had A&C _inf 466518 h-pg / ml. Subjects given 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin as an experimental composition after eating very fatty foods (treatment regimen B, test) reached a plasma concentration for dextromethorphan with an average of C _maK from _12,757 pg / ml (132% of treatment regimen A ) after 5.74 h (104% of treatment regimen A) and had A&S _in f 472064 h-pg / ml (117% of treatment regimen A).

Plasma concentrations of guaifenesin are depicted in FIG. 37. The obtained pharmacokinetic data are given in table. 68-70. Subjects given 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide as an experimental composition after overnight fasting (treatment regimen A, standard) achieved an average of C _max 2030 ± 882 ng / ml (mean ± standard deviation) for 1.61 ± 1 , 15 h and had AiS _in f 8128 ± 3497 h-ng / ml. Subjects given 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide as an experimental composition after eating very fatty foods (treatment regimen B, test) achieved an average of C _{max of} 1825 ± 789 pg / ml (98.0 ± 40.3% of the regimen) treatment A) of 2.93 ± 1.44 hours (248 ± 164% to treatment A) and had AiS _yn f 7093 ± 2787 ng-hr / ml (92.9 ± 23.6% to treatment A).

Table 68. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide in the form of an experimental composition, after night fasting (Treatment regimen A, Standard) Subject Smake (nanogram / ml T _m ax (hour) fisc, (hour ng / ml) AiSif, (hour nanogram / ml) Half period (hour) Clearance B / hour Middle 2030 1,61 8107 8128 1.15 172 Medium 1760 1,5 111 7789 1,04 154 Standard deviation 882 1.15 3485 3497 0.356 65.7 Standard error 151 0.198 598 600 0,0611 11.3 % SU 43,4 71,4 43.0 43.0 30.97 38.1

Table 69. Pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide in the form of an experimental composition, after ingestion of very fatty foods (Treatment regimen B, Test)

Subject Smake (nanogram / ml Tmax (hour) AiSch, (hnanogram / ml) ACSdaf, (hnanogram / ml) Half period (hour) Clearance b / h Middle 1825 2.93 7077 7093 0.849 190 Medium 1520 3 6201 6228 0.854 193 Standard deviation 789 1.44 2788 2787 0.115 60.6 Standard error 133 0.243 471 471 0.0194 10,2 % SU 43,2 49.1 39,4 39.3 13.5 31.9

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Table 70. The relationship between the pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide, after eating very fatty foods, on the one hand, and after night fasting, on the other. (%). Subject Smake Tmax fox AiSif, Half period Clearance Middle 98.0 248 92.9 92.9 79.5 114 Median 89.8 250 88.9 88.3 79.5 113 Standard deviation 40.3 163.7 23.7 23.6 19,4 26.8 Standard error 6.92 28.1 4.07 4.05 3.33 4.60 % SU 41.1 66.0 25.6 25,4 24.4 23.5

Plasma concentrations of dextromethorphan are depicted in FIG. 38. The obtained pharmacokinetic data are given in table. 71-73. Subjects given 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin as an experimental composition after overnight fasting (treatment regimen A, standard) achieved a plasma concentration of dextromethorphan in the average Smake Yu722 ± 15966 pg / ml for 6.23 ± 3.55 h and had AIS _in f 466518 ± 987204 h-pg / ml. Subjects given 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin as an experimental composition after eating very fatty foods (treatment regimen B, test) reached a plasma concentration for dextromethorphan of an average C _maK from 12757 ± 17914 pg / ml (132 ± 69 , 8% of treatment regimen A) for 5.74 ± 2.27 h (104 ± 43.4% of treatment regimen A) and had A&S _in f 472064 ± 977485 h-pg / ml (117 ± 61.5% of treatment regimen A )

Table 71. Pharmacokinetic parameters of dextromethorphan, after administration to normal volunteers of 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin in the form of an experimental composition, after night fasting Treatment regimen A (Standard)

Subject Smake (picogram / ml Tmax (hour) leaf, (chaspicogram / ml) AisSchf, (chaspicogram / ml) Half period (hour) Clearance b / h Middle 10722 6.23 372897 466518 13.8 2343 Medium 3020 6.0 33799 34134 8.52 1287 Standard deviation 15966 3,55 753127 987204 12.8 3352 Standard error 2738 0.609 129160 169304 2.19 575 % SU 149 57.0 202 212 92.7 143

Table 72. Pharmacokinetic parameters of dextromethorphan, after administration to normal volunteers of 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin in the form of an experimental composition, after ingestion of very fatty foods - Treatment regimen B (Test) Subject Smake (picogram / ml Tmax (hour) fox, (chaspicogram / ml) ALSdaf, (chaspicogram / ml) Half period (hour) Clearance b / h Middle 12757 5.74 381391 472064 13.5 2246 Medium 3470 5 37515 37808 7.98 1174 Standard deviation 17914 2.27 753249 977485 133 2905 Standard error 3028 0.384 127322 165225 2,3 491 % SU 140 39.6 198 207 98.5 129

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Table 73. The relationship between the pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin, after taking greasy food , on the one hand, and after night fasting, on the other, (%). Subject S _m ax Tmax AiSm, fox ^, Half period Clearance Middle 132 104 118 117 98.6 one hundred Median 124 one hundred 106 106 one hundred 94.4 Standard deviation 69.8 43,4 62,2 61.5 18.8 35.6 Standard error 12.0 7.5 10.7 10.5 3.22 6.10 % SU 52.8 41.9 52.8 52.6 19.0 35.7

In conclusion, it should be noted that the presence of food has no effect on the absorption of guaifenesin from the experimental tablet. Food affects the rate of absorption of dextromethorphan from a tablet of the experimental composition (a slight increase in the rate of absorption), but not the degree of absorption.

Example 21

In order to determine the relative bioaccumulation of guaifenesin and dextromethorphan in an experiment with normal volunteers, the relative bioaccumulation was compared: from a modified release experimental composition containing guaifenesin and dextromethorphan, on the one hand, and from standard products of guaifenesin and dextromethorphan, on the other, according to an open-label system in the form of multiple doses, randomized, by a tri-cross-sectional study of 36 subjects.

Subjects were randomized and were included in one of three experimental groups. Group 1 received a controlled release product of guaifenesin in the form of 1200 mg of mucinex (Misseh) plus 60 mg of dextromethorphan hydrobromide (administered in 30 mg doses every 6 hours) with 240 ml of water after an overnight fast and 12 hours later for 11 twelve-hour periods dosing (treatment regimen A, standard). Group 2 received a controlled release product of guaifenesin in the form of 1200 mg of mucinex (Misseh) plus 60 mg of dextromethorphan hydrobromide (administered as 20 mg doses every 4 hours) with 240 ml of water after an overnight fast and 12 hours later, over 11 twelve-hour dosing periods (treatment regimen B, standard). Group 3 received an experimental, controlled-release tablet containing 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide, with 240 ml of water, after nightly fasting and another 12 hours later, for 11 twelve-hour dosing periods (treatment regimen C, test). the experiment between doses had a 14-day interval.

Blood samples were taken (7 ml each with the addition of sodium heparin as an anticoagulant) day 1 - before the noon dose, day 4 - before the noon dose and day 5 - before the noon dose for all three experimental groups. On the 6th day of treatment, subjects of experimental group A were bled before and after dosing after 0.5; 0.75; one; 1.5; 2; 3; 4; 5; 6; 6.5; 6.75; 7; 7.5; 8; nine; 10; eleven; 12; 14; sixteen; 24; 36; 48; 72 and 96 hours. Subjects of experimental group B took blood before dosing and after dosing after 0.5; 0.75; one; 1.5; 2; 3; 4; 4,5; 4.75; 5; 5.5; 6; 7; 8; 8.5; 8.75; nine; 9.5; 10; eleven; 12; 14; sixteen; 24; 36; 48; 72 and 96 hours. On the 6th day of treatment, subjects of the experimental group C took blood before dosing and after dosing after 0.5; 0.75; one; 1.5; 2; 3; 4; 5; 6; 8; 10; 12; 14; sixteen; 24; 36; 48; 72 and 96 hours (the total amount of blood lost during the analysis of guaifenesin and dextromethorphan was 588 ml).

Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Misseh) together with 60 mg of dextromethorphan hydrobromide in two 30 mg doses after 6 hours each (treatment regimen A, standard) reached a plasma concentration of guaifenesin on average C _{max of} 1935 ng / ml via 1.27 hours after the last dose (121 hours after the first dose) and had a C _{min of} 75.5 ng / ml. With an _{average of} 631 ng / ml and an _{AIS of a} stationary state of 7540 h-ng / ml. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Misseh) together with 60 mg of dextromethorphan hydrobromide in three 20 mg doses after 4 hours each (treatment regimen B, standard) achieved a steady-state plasma concentration of guaifenesin on average C _max 1938 ng / ml 0.850 hours after the last dose (121 hours after the first dose) and had a C _{min of} 59.6 ng / ml. With an _{average of} 618 ng / ml and an AIS of a _steady state 7403 h-ng / ml. Subjects given 1200 mg of guaifenesin as an experimental composition, as well as 60 mg of dextromethorphan hydrobromide (treatment regimen C, test) achieved a steady-state plasma concentration of guaifenesin on average C _{max of} 1780 ng / ml 1.35 h after the last dose (121 h after the first dose) and had a C _{min of} 18.2 ng / ml. With _media 601 ng / ml of _Stutz and AIS state _N ary 7138 hr-ng / ml.

Subjects given 60 mg of dextromethorphan hydrobromide in the form of 30 mg of Vika cough medicine 44 (Hbskz Gopshya 44 Soschf Messshe) together with 1200 mg of guaifenesin in the form of mucinex (Misseh), and after 6 hours another 30 mg dose of dextromethorphan hydrobromide (regimen treatment A, standard), reached a steady-state plasma concentration for dextromethorphan average C _max

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17960 pg / ml for 5.03 h after the last dose (125 h after the first dose) and had C _min 11949 pg / ml. With _avg 15167 pg / ml and AiStationary state 181904 h-pg / ml. Subjects given 60 mg of dextromethorphan hydrobromide in the form of 20 mg of Vika's cough medicine 44 (U1sk'8 Roshsh1a 44 SoshchN Mesiste) every 4 hours together with 1200 mg of guaifenesin in the form of mucinex (Misseh) (treatment regimen B, standard) reached the steady-state plasma concentration for dextromethorphan averaged C _max 17251 pg / ml 5.91 hours after the last dose (126 hours after the first dose), and had C _min 11018 pg / ml. With _avg. 14097 pg / ml and AiStationary state 169160 h-pg / ml. Subjects given 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin as an experimental composition (treatment regimen C, test) achieved a steady-state plasma concentration of dextromethorphan on average C _max 17213 pg / ml 5.10 hours after the last dose (125 hours) after the first dose), and had a C _min 10978 pg / ml, etc. With _cFe 14609 pg / ml and _{a steady state} Ais 175,309 hr-pg / ml.

Plasma concentrations of guaifenesin are depicted in FIG. 39 and 40. The obtained pharmacokinetic data are given in table. 74-76. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Misseh) together with 60 mg of dextromethorphan hydrobromide in two 30 mg doses after 6 hours each (treatment regimen A, standard) reached a steady-state plasma concentration for guaifenesin on average C _max 1935 ± 746 ng / ml ± 0.854 for 121 hours after the first dose (1.27 hours after the last dose) had a C _min and 75.7 ± 73.9 ng / ml, _media C 631 ± 212 ng / ml of _CT and AIS Discount _P Nogo conditions 7540 ± 2570 h-ng / ml. Subjects who were given 1200 mg of guaifenesin in the form of mucinex (Mistech) together with 60 mg of dextromethorphan hydrobromide in three 20 mg doses after 4 hours each (treatment regimen B, standard) achieved a steady-state plasma concentration of guaifenesin on average C _max 1938 ± 637 ng / ml for 1.21 ± 0.463 h after the first dose (0.850 h after the last dose) and had a C _{min of} 59.6 ± 51.9 ng / ml. With _media 618 ± 205 ng / ml of _CT and AIS states Nogo Discount _F 7403 ± 2474 ng-h / mL. Subjects given 1200 mg of guaifenesin as an experimental composition also containing 60 mg of dextromethorphan hydrobromide (treatment regimen C, test) reached a plasma concentration of guaifenesin on average C _{max of} 1780 ± 633 ng / ml for 121 ± 0.864 hours after the first doses (1.35 h after the last dose) and had a C _{mitt of} 18.2 ± 18.3 ng / ml, With a _{medium of} 601 ± 189 ng / ml and an A & S stationary state 7138 ± 2268 H-NG / ML.

Table 74. Stationary pharmacokinetic administration to normal volunteers of 1200 (Mistech) in an amount of 11 doses, every 12 hours of dextromethorphan in the form of 30 mg of Medication Βι Soi§i Mesiste), in an amount of 22 doses, each ( Subject C _th (cngr / ml Cmin (ngr / ml) Smake (ngr / ml) Tmax (hour) Middle 7540 75,5 1935 122 Wed dean. 7366 59.0 1910 121 Art .. off 2570 73.9 746 0.854 Art. a mistake 441 12.7 128 0.146 % SU 34.1 97.9 38.6 0.704

parameters of guaifenesin, after > mg of guaifenesin in the form of Mucinex zs, and 60 mg of hydrochloride bromide from Cough 44 (U1sk '$ Roppi1a 44 6 hours (Treatment regimen A, Standard) Serini (ngr / ml) % P £ (%) % Oscillations (%) b ₂ (hour ¹ ) t _1/2 (hour) 631 296 5828 0.270 3.11 614 297 2962 0.226 3.07 212 56.2 6702 0.151 1.26 36,4 9.64 1149 0,026 0.217 33.7 19.0 115 55.8 40.6

Table 75. Stationary pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech) in the amount of AND doses, every 12 hours, and 60 mg of dextromethorphan hydrobromide in the form of 20 mg of Vika's Cough 44 Medication (Hysk's Gogshi 44a Soy § Less), in an amount of 22 doses, every 4 hours (Treatment regimen B, Standard)

Subject "4ngr / ml Cmin (ngr / ml) Smake (ngr / ml) Tmax (hour) Serini (ngr / ml) % Ρί £ (%) % Oscillations (%) b ₂ (hour ¹ ) T1 / 2 (hour) Middle 7403 59.6 1938 121 618 313 7215 0.269 3.22 Wed dean. 7230 36.1 1910 121 603 294 3173 0.227 3.05 Art., Off 2474 51.9 637 0.463 205 72 8948 0.164 1.36 Art. a mistake 424 8.90 109 0,079 35,2 12,4 1535 0,028 0.232 % SU 33,4 87.1 32.9 0.383 332 23,2 124 61.0 42.1

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Table 76. Stationary pharmacokinetic parameters of guaifenesin, after administration to normal volunteers of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide in the form of an experimental composition, 11 doses, every 12 hours (Treatment regimen C, Standard) Subject C _a (cngr / ml Cmin (ngr / ml) Smake (ngr / ml) Tmax (hour) Average (ngr / ml) % Ρί £ (%) % Caleb (%) b ₂ (hour ¹ ) T1 / 2 (hour) Middle 7138 18.2 1780 121 601 292 14215 0.431 1.91 Wed Dean. 6992 13.7 1770 121 583 291 10240 0.414 1,67 Art., Off 2268 183 633 0.864 189 45,2 11362 0.177 0.832 Art. a mistake 395 3.18 110 0.150 32.8 7.88 1978 0,031 0.145 % SU 31.8 101 35.6 0.712 31,4 153 79.9 41.1 43.6

Plasma concentrations of dextromethorphan are depicted in FIG. 41 and 42. The obtained pharmacokinetic data are given in table. 77-79. Subjects given 60 mg of dextromethorphan hydrobromide in the form of 30 mg of Vika's cough medicine 44 (Uyk'z Eopni1a 44 SoyuI MesNste) together with 1200 mg of guaifenesin in the form of mucinex (Mistech), and after 6 hours another 30 mg dose of dextromethorphan hydrobromide ( treatment regimen A, standard), the steady-state plasma concentration for dextromethorphan reached an average of C _max 17960 ± 37537 pg / ml for 125 ± 2.94 hours after the first dose (5.03 hours after the last dose) and had C _min 11949 ± 28101 pg / ml, With _avg 15167 ± 33349 pg / ml and A&S _ST stationary state 181904 ± 400226 h-pg / ml. Subjects who were given 60 mg of dextromethorphan hydrobromide in the form of three 20 mg doses of Vika's cough medicine 44 (Hysk'S Egty1a 44 SoyuI MeShste) every 4 hours together with 1200 mg of guaifenesin in the form of mucinex (Mistech) (treatment regimen B, standard), reached a steady-state plasma concentration for dextromethorphan on average C _max 17251 ± 39562 pg / ml 126 ± 1.73 h after the first dose (5.91 h after the last dose) and had C _min 11018 ± 26007 pg / ml, C _av 14097 ± 33537 pg / ml and AiStationary state 169160 ± 402449 h-pg / ml. Subjects given 60 mg of dextromethorphan hydrobromide and 1200 mg of guaifenesin as an experimental composition (treatment regimen C, test) reached a steady-state plasma concentration for dextromethorphan in the average Smake of 17213 ± 33703 pg / ml after 125 ± 1.62 h (5, 10 hours after the last dose) and had C _min 10978 ± 24713 pg / ml. Sred 14609 ± 30804 pg / ml and A & S stationary state 175309 ± 369653 h-pg / ml.

Table 77. The stationary pharmacokinetic parameters of dextromethorphan, after the administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech) in the amount of 11 doses, every 12 hours, and 60 mg of dextromethorphan hydrobromide in the form of 30 mg of Vika Cough Medicine 44 (U1sk'z Gopshya 44 Sed MesNste), in an amount of 22 doses, every 6 hours (Treatment regimen A, Standard) Subject C85 (cngr / ml Cmin (ngr / ml) C _M ax (ngr / ml) Tmax (hour) Sfbdai (ngr / ml) % Ρί £ (%) % Caleb (%) b ₂ (hour ¹ ) T _w (hour) Middle 181904 11949 17960 125 15167 56.4 80.0 0.108 8.67 Wed dean. 39400 2270 4100 124 3312 53.1 73.1 0.113 6.13 Art., Off 400226 28101 37537 2.94 33349 19.7 37.7 0,045 8.50 Art. a mistake 68638 4819 6438 0.503 5719 3.38 6.47 0.008 1.46 % SU 220 235 209 2,35 220 35.0 47.2 41,4 98.1

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Table 78. Stationary pharmacokinetic parameters of dextromethorphan,

after the administration to normal volunteers of 1200 mg of guaifenesin in the form of Mucinex (Mistech) in an amount of 11 doses, every 12 hours, and 60 mg of dextromethorphan hydrobromide in the form of 20 mg of Vika's Cough 44 Medication (Uyuk's Roppi 44a Soigk Mebute), in an amount 22 doses, every 4 hours (Treatment regimen B, Standard) Subject C _a (cngr / ml Cmin (ngr / ml) Smake (ngr / ml) Tmax (hour) Ssrenm (ngr / ml) % P £ (%) % Oscillations (%) Bh (hour ¹ ) (hour) Middle 169160 11018 17251 126 14097 57.2 78,4 0,090 11.8 Wed Dean. 36778 2280 4250 126 3065 58.7 75.6 0,075 9.27 Art .. off 402449 26007 39562 1.73 33537 19.0 32.1 0,054 9.54 Art. a mistake 69019 4460 6785 0.297 5752 3.26 5.51 0.009 1,64 % SU 238 236 229 1.38 238 33,2 41.0 59.7 80.9

Table 79. Stationary pharmacokinetic parameters of dextromethorphan after administration to normal volunteers of 1200 mg of guaifenesin and 60 mg of dextromethorphan hydrobromide in the form of an experimental composition, in the amount of 11 doses, every 12 hours (Treatment regimen B, Standard) Subject C _a (cngr / ml Cmin (ngr / ml) Smake (ngr / ml) Tmax (hour) Ssreaia (ngr / ml) % P £ (%) % Oscillations (%) b ₂ (hour ¹ ) T1 / 2 (hour) Middle 175309 10978 17213 125 14609 74.0 129 0,112 7.84 Wed dean. 37663 1855 4355 125 3139 73,4 126 0.113 6.12 Art .. off 369653 24713 33703 1,62 30804 23,2 56.3 0,042 5.71 Art. a mistake 64348 4302 5867 0.282 5362 4.04 9.80 0.007 0,994 % SU 211 225 196 1.30 211 31,4 43.6 37.6 72.8

In conclusion, it should be noted that guaifenesin in the form of an experimental tablet is a bioequivalent preparation of mucinex (Mistech) in terms of C _max and AIC ₈₈ , since all 90% confidence intervals are in the range of 80-125%. Dextromethorphan hydrobromide in the form of an experimental tablet is bioequivalent to dextromethorphan hydrobromide in doses of 30 mg every 6 hours and 20 mg every 4 hours according to the parameters C _max and ACS ₈₈ , since all 90% confidence intervals are within 80-125%.

Other aspects of the implementation and use of the invention will be apparent to those skilled in the art after reviewing the specifications and practices for using the invention set forth herein. Specifications and examples should be considered as an example only in the aspect of the true capabilities and spirit of the invention in accordance with the following claims. Specialists should bear in mind that within the scope of this invention and in accordance with the following claims, various variations and modifications are permissible.

List of Abbreviations

AiS ₈₈ - 8! Eabu-a! A! E tach1itit p1azta sopsep! Hyop - Stationary maximum plasma concentration

ACSinf - The area of plasma concentration against the time curve from 0 to infinity

SEM - SiS Geey! reg pnpi! e - (number) cubic feet per minute

OS - Opes! Sotrzezzeb - Directly Pressed

ΕϋΑ - Eob apb Aegid Abppszyayop - Food and Drug Administration (U.S.)

HPEC - liquid chromatography high pressure / resolution

ΙΚ - 1tteb1a! E Ke1ease 1ogti1a! Yup - immediately releasing composition

RK U-mixer - Reitsk Ke11u U-Yepbeg - Patrick Kelly U-mixer

Κδϋ - Ке1ай νε Mapbagbag Оеу1а! Юп - Relative standard deviation

-67007156 ssi - s! Gopd-SOB Ip'y - Unit Strong-Koba

S / A - Yo! LuPaYe (no data, not available)

EXCEPT - EXCEPTION1 EGTI1 - Addendum to the American Pharmacopoeia

BPM - VEUO1i! UP8 Reg Mt! E - RPM ZV - Ziyasheb Vеeеаge Гогти1а! УП - slow-release composition from Р - Ма! Епе1! § кedsюйопк оГ Т1е Ish! USP specifications

SV layer - Slow release layer

HB layer - Immediately releasing layer% SU -% SoeGPS1ep1 Uapayop -% coefficient of variation

Claims (54)

CLAIM 1. A drug delivery system in which a unit dosage form comprises a slow release portion comprising guaifenesin, an optionally second drug and a slow release matrix comprising a hydrophilic polymer and a water insoluble polymer; the immediate releasing part, including guaifenesin, where guaifenesin, in a single dose, is bioavailable at a therapeutically effective level for at least 12 hours 2. The drug delivery system according to claim 1 is characterized in that said arbitrary drug is selected from dextromethorphan and pseudoephedrine. 3. The drug delivery system according to claim 2 is characterized in that said arbitrary drug is contained only in the slow release part. 4. The drug delivery system according to claim 2 is characterized in that said arbitrary drug is contained only in the immediately releasing portion. 5. The drug delivery system according to claim 2 is characterized in that said arbitrary drug is contained in both the immediate-release part and the slow-release part. 6. The system according to claim 2 is characterized in that the slow-release matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of about 1: 1-9: 1, about 3: 2-6: 1, and about 2: 1-4: one. 7. The system according to claim 2 is characterized in that the total amount of guaifenesin is in the range of 500-1300 mg. 8. The system according to claim 7 is characterized in that the total amount of guaifenesin in the indicated unit dose form is in the range of about 600-1200 mg. 9. The system according to claim 8 characterized in that said unit dosage form of guaifenesin for a C _max that is bioequivalent C _max determined Eel (FDA Office of the Food and Drug Administration) for the tablets, immediate release guaifenesin force - a third of the dose. 10. The system according to claim 9 is characterized in that said unit dose form contains 1200 mg of guaifenesin. 11. The system according to claim 10 is characterized in that C _max for guaifenesin is selected in the range of 10003000, 1200-3500, 1350-3000 and 1450-2750 ng / ml. 12. The system according to claim 9 is characterized in that said unit dose form contains 600 mg of guaifenesin. 13. The system according to claim 12 is characterized in that C _max for guaifenesin is selected in the range of 320-1875, 400-1500, 500-1375 and 625-1250 ng / ml. 14. The system according to claim 8 is characterized in that the therapeutically effective level is measured by Cmin. 15. The system according to claim 14 characterized in that the unit dosage form has See for guaifenesin _in, which is bioequivalent C _min determined Eel for tablets, immediate release guaifenesin and containing 400 mg of guaifenesin. 16. The system according to claim 14 is characterized in that the _Smin for guaifenesin is selected in the range of 35-75, 4070, 45-65 and 50-60 ng / ml. 17. The system according to claim 8 is characterized in that the therapeutically effective level is measured by AISinf (the region of plasma concentration against the time curve from 0 to infinity). 18. The system according to claim 17 is characterized in that said unit dose form contains 1200 mg of guaifenesin. 19. The system according to claim 18 is characterized in that AIS ^ for guaifenesin is selected in the range of 400012500, 5000-10000, 5500-9500 and 6000-9000 h-ng / ml. 20. The system according to claim 8 is characterized in that said unit dose form contains 600 mg of guaifenesin. - 68 007156 21. The system according to claim 20 is characterized in that AISinf for guaifenesin is selected in the range of 20006250, 2500-5000, 2250-4750 and 3000-4500 h-ng / ml. 22. The system according to claim 2 is characterized in that the immediately releasing portion further contains microcrystalline cellulose, sodium starch glycolate and magnesium stearate. 23. The system according to claim 2 is characterized in that the ratio of the total amount of guaifenesin to dextromethorphan is in the range of about 1: 1-30: 1 by weight. 24. The system according to claim 2 is characterized in that the ratio of the total amount of guaifenesin to dextromethorphan is in the range of about 8: 1-12: 1 by weight. 25. The system according to claim 2 is characterized in that the ratio of the total amount of guaifenesin to pseudoephedrine is in the range of about 1: 1-30: 1 by weight. 26. The system according to claim 2 is characterized in that the ratio of the total amount of guaifenesin to pseudoephedrine is in the range of about 8: 1-12: 1 by weight. 27. The system according to claim 1 is characterized in that the ratio of the amount of immediately released guaifenesin to the amount of delayed-release guaifenesin is in the range of about 1: 1-1: 15 by weight. 28. The system according to claim 1 is characterized in that the ratio of the amount of immediately released guaifenesin to the amount of delayed-release guaifenesin is in the range of about 2: 3-1: 11 by weight. 29. The system according to claim 1 is characterized in that approximately 60% of the particles of guaifenesin used to prepare the unit dose form have sizes in the range of about 150 microns to 2.0 mm. 30. The system according to claim 1 is characterized in that the unit dose form has C _max for guaifenesin of at least about 1900 ng / ml and AIS _in f for guaifenesin of at least 7000 h-ng / ml. 31. The system according to claim 1 is characterized in that the unit dosage form has a C _max for guaifenesin of at least about 1000 ng / ml and AIS _in f for guaifenesin of at least 3500 h-ng / ml. 32. The system according to claim 1 is characterized in that according to the analysis of blood serum, the half-period of a unit dose form is at least 3 hours. 33. The system according to claim 1 is characterized in that the slow-release part comprises about 75-95 wt.% Guaifenesin, about 1-15% dextromethorphan, about 0.5-10% hydrophilic polymer and about 0.5-2.5% water insoluble polymer by weight. 34. The system according to claim 1 is characterized in that the unit dose form includes immediate-release and slow-release parts, each of which essentially consists of flat adjacent layers forming a two-layer tablet. 35. The system according to claim 1 is characterized in that the bioaccumulation of dextromethorphan at a therapeutically effective level occurs at least 12 hours after a single dose. 36. The system according to claim 1 is characterized in that the slow release portion comprises about 75-80 wt.% Guaifenesin, about 5-10 wt.% Dextromethorphan, about 3-6 wt.% Hydroxypropyl cellulose and about 1-1.5 wt. % acrylic resin. 37. The system according to claim 1 is characterized in that the unit dose form has C _max for guaifenesin of approximately 1600-2500 ng / ml and AISinf for guaifenesin of approximately 5600-8750 h-ng / ml. 38. The system according to claim 1 is characterized in that the unit dose form has a C _max for guaifenesin of approximately 800-1250 ng / ml and AIS _in f for guaifenesin of approximately 2800-4375 h-ng / ml. 39. The system according to claim 1 is characterized in that the unit dose form includes a capsule that contains the immediate-release and slow-release parts in a discrete or associated form. 40. The system according to claim 7 is characterized in that it is approximately equally effective when administered to a patient on an empty or full stomach. 41. The system according to claim 7 is characterized in that said unit dose form has a plasma concentration profile of guaifenesin shown in FIG. 10. 42. A drug product, which includes an immediately releasing part, including guaifenesin and, optionally, a second drug, said part providing bioaccumulation of guaifenesin in the stomach of a subject; and a delayed release portion comprising guaifenesin and, optionally, a second drug, wherein the ratio of the immediately released guaifenesin to the sustained release guaifenesin is in the range of about 1: 1-1: 15; in the human body, the product provides C _max guaifenesin equivalent to C _max , which is achieved by dosing the first 3 doses of an approved RIA composition containing one third of the amount of guaifenesin every 4 hours for a period of 12 hours, and according to a blood serum analysis, the product provides a therapeutically effective body bioaccumulation of guaifenesin for at least 12 hours after a single dose. 43. The drug product according to paragraph 42 is characterized in that the second drug is selected from dextromethorphan or pseudoephedrine. - 69 007156 44. The drug product according to item 43 is characterized in that the immediately releasing and slow-release parts, both essentially include flat adjacent layers forming a two-layer tablet. 45. The drug product according to item 43 is characterized in that the slow release portion is coated with a layer of the immediate release portion. 46. The drug product according to item 43 is characterized in that the product includes a capsule that contains immediate-release and slow-release parts. 47. A method of treating a subject in need of temporary relief from accumulation of bronchial mucus comprises administering to the subject a therapeutically effective amount of one of the drug delivery systems according to claim 2. 48. The method according to item 47 is characterized in that the drug delivery system is administered orally. 49. A method of treating a subject in need of temporary relief from bronchial mucus and cough, comprising administering to the subject a therapeutically effective amount of a modified releasing drug product comprising guaifenesin and dextromethorphan in an immediately releasing composition providing for bioaccumulation of guaifenesin in the stomach of the subject; and guaifenesin, dextromethorphan, and a slow release matrix — into the slow release part, where the slow release matrix includes a hydrophilic polymer and a water-insoluble polymer, where the weight ratio of the hydrophilic polymer to the water-insoluble polymer is about 1: 1-9: 1, where human body, the product provides a C _max of guaifenesin equivalent C _max which is achieved when dispensing the first 3 doses approved ΕΌΛ composition comprising a third quantity of guaifenesin, every 4 hours of period of 12 hours and by analysis of blood serum provides a product in humans, a therapeutically effective bioavailability of guaifenesin for at least 12 hours after a single dose. 50. A method of treating a subject in need of temporary relief from bronchial mucus and nasal congestion includes administering to the subject a therapeutically effective amount of a modified release drug product comprising guaifenesin in the immediate-release composition providing bioavailability of guaifenesin in the stomach of the subject; and guaifenesin, pseudoephedrine and a slow release matrix in the slow release part, where the slow release matrix includes a hydrophilic polymer and a water-insoluble polymer, where the weight ratio of the hydrophilic polymer to the water-insoluble polymer is about 1: 1-9: 1, where the product provides in the human body, C _max guaifenesin, equivalent to C _max , which is achieved by dosing the first 3 doses of an approved EEA composition containing one third of the amount of guaifenesin every 4 hours a period of 12 hours and, according to a blood serum analysis, the product provides a therapeutically effective bioaccumulation of guaifenesin in the human body for at least 12 hours after a single dose. 51. A drug delivery system that includes a slow release portion comprising guaifenesin, dextromethorphan, and a slow release matrix comprising a hydrophilic polymer and a water insoluble polymer; and an immediate release portion comprising guaifenesin and dextromethorphan; where, according to a blood serum analysis, the bioaccumulation of guaifenesin at a therapeutically effective level occurs within at least 12 hours after a single dose, and where the unit dose form in the human body shows C _max above 640 ng / ml and T _max within 8 hours, and C _{min is} maintained above 80 ng / ml for 12 or more hours. 52. A drug delivery system that includes a slow release portion comprising guaifenesin, pseudoephedrine and a slow release matrix comprising a hydrophilic polymer and a water insoluble polymer; and an immediate release portion comprising guaifenesin; where, according to a blood serum analysis, the bioaccumulation of guaifenesin at a therapeutically effective level occurs within at least 12 hours after a single dose, and where the unit dose form in the human body shows C _max above 640 ng / ml and T _max within 8 hours, and C _{min is} maintained above 80 ng / ml for 12 or more hours. 53. The drug delivery system, the unit dosage form of which includes a slow release portion comprising guaifenesin, pseudoephedrine and a slow release matrix comprising a hydrophilic polymer and a water insoluble polymer; an immediate release portion comprising guaifenesin; however, bioaccumulation of guaifenesin at a therapeutically effective level occurs for at least 12 hours after a single dose. 54. A drug delivery system, the unit dosage form of which includes a slow release portion comprising guaifenesin, dextromethorphan, and a slow release matrix comprising a hydrophilic polymer and a water insoluble polymer; and an immediate release portion comprising guaifenesin and dextromethorphan; however, bioaccumulation of guaifenesin at a therapeutically effective level occurs for at least 12 hours after a single dose.