RU2540509C1 - Drug - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: drug preparation contains a combination of phenylephrine hydrochloride (or an equivalent amount of the other pharmaceutically acceptable form of phenylephrine) and paracetamol.

EFFECT: combining two active ingredients provides effective relief of cold and influenza symptoms.

14 cl, 5 dwg, 4 ex, 10 tbl

Description

FIELD OF THE INVENTION

In a preferred form, this invention relates to a medicament for treating congestion of the upper respiratory tract due to swelling of the mucous membranes, containing paracetamol and phenylephrine hydrochloride as active ingredients. In some embodiments of the invention, phenylephrine hydrochloride may be substituted with another chemical form of phenylephrine.

BACKGROUND

Congestion of the upper respiratory tract due to swelling of the mucous membranes caused by infections such as the common cold and flu can be accompanied by many unpleasant symptoms. These include nasal congestion, increased discharge from the sinuses, headache, muscle pain, fever, and poor health. An object of the preferred embodiment of the present invention is to make some progress by proposing a combination of paracetamol and phenylephrine hydrochloride to relieve at least some people of at least some of the above symptoms.

Paracetamol is a well-known over-the-counter painkiller, which is usually taken in doses of 650 mg or 1000 mg in the form of 2 tablets of 500 mg or 325 mg each. Phenylephrine hydrochloride is a known decongestant, which is usually taken at a dose of 10 mg as a single tablet, taken separately, or as 2 tablets of 5 mg each when taken in combination with other agents such as paracetamol.

Combinations of paracetamol and phenylephrine hydrochloride are known. For example, Codral ™ PE Cold & Flu + Cough contains 500 mg paracetamol + 5 mg phenylephrine hydrochloride + 10 mg dextromethorphan hydrobromide in capsule form. This product must be taken 2 capsules at a time to reach an adult dose of 1000 mg paracetamol + 10 mg phenylephrine hydrochloride + 20 mg dextromethorphan hydrobromide every 4-6 hours.

Another example is Lemsip ™ Cold & Flu, available in capsule form containing 25 mg of caffeine + 500 mg of paracetamol + 6.1 mg of phenylephrine hydrochloride each (equivalent to 5 mg of phenylephrine free base). This product must be taken 2 capsules at a time to achieve a double adult dose every 4-6 hours.

Another example is Panado ™ PE Sinus Relief, available in capsule form containing 500 mg paracetamol + 5 mg phenylephrine hydrochloride. To reach the adult dose, take 2 capsules every 4-6 hours.

Another example is the No Drowse Decolgen ™ drug known in some Asian countries, available in tablet form containing 500 mg paracetamol + 10 mg phenylephrine hydrochloride each. To reach an adult dose, take 1 tablet every 6 hours.

As indicated above, the normal adult dose of phenylephrine hydrochloride is 10 mg and is taken in 2 dosage units, such as capsules or tablets. A dose of 10 mg phenylephrine hydrochloride provides 8.1 mg of phenylephrine free base. However, higher doses, such as 12.2 mg of phenylephrine hydrochloride, are known to provide an equivalent of 10 mg of the free base. Thus, a generally accepted dose is an amount sufficient to provide an equivalent of 8.1 mg to 10 mg of the free base. The recommended frequency of taking the dose is 3-4 times a day (Martindale 28 ^th Edition) or every 4 hours (Drug Tx, 4 ^th Edition).

Patent No. WO 2009/012590 (Kingsway) on pages 21 and 29 refers to tablets containing 50 mg ibuprofen + 80 mg paracetamol + 5 mg phenylephrine. However, there is no description of whether these tablets are intended for adults or children, and whether 2 tablets are necessary to ensure that 10 mg of phenylephrine is obtained.

Although a 10 mg dosage of phenylephrine in combination with 1000 mg of paracetamol is known, it was not previously reported that paracetamol improves the absorption of phenylephrine hydrochloride so much that the dose of phenylephrine can be significantly reduced. This important discovery allows at least many patients to take substantially lower doses of phenylephrine hydrochloride without compromising treatment effectiveness and without the risk of undesirable side effects, as when taking substantially large doses.

SUMMARY OF THE INVENTION

First of all, this invention provides a medicament for the treatment of congestion of the upper respiratory tract due to swelling of the mucous membranes, containing the following combination:

- from about 2 mg to about 4 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- from about 250 mg to about 500 mg of paracetamol; for an adult to take a total dose of:

- from about 4 mg to about 8 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- from about 500 mg to about 1000 mg of paracetamol.

In some cases, this drug is offered in the form of a dosage unit containing:

a) from about 2 mg to about 3.75 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine) and from about 325 mg to about 500 mg of paracetamol, for an adult to take two such units at a time to produce a drug in an amount twice as large as that contained in one unit; or

b) from about 2.9 mg to about 4 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine) and from about 250 mg to about 325 mg of paracetamol, for an adult to take two such units at a time to obtain a drug in an amount twice as large as that contained in one unit.

In some cases, this drug is offered in the form of a dosage unit containing:

- approximately 2.5 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 500 mg of paracetamol,

for an adult to take two such units at a time to obtain a drug in an amount two times larger than that contained in one unit.

In some cases, this drug is offered in the form of a dosage unit containing:

- approximately 3 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 500 mg of paracetamol,

for an adult to take two such units at a time to obtain a drug in an amount two times larger than that contained in one unit.

In some cases, this drug is offered in the form of a dosage unit containing:

- approximately 3 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 325 mg of paracetamol,

for an adult to take two such units at a time to obtain a drug in an amount two times larger than that contained in one unit.

In another aspect, the invention describes the use of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine) and paracetamol for the manufacture of a medicament for the treatment of upper respiratory tract congestion due to edema of the mucous membranes containing a combination of these substances with excipients, wherein the medicament contains phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine ) and paracetamol in a ratio suitable for supplying an adult with the following amount of substances:

- from about 4 mg to about 8 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- from about 500 mg to about 1000 mg of paracetamol.

Preferably, the drug is provided in the form of tablets, capsules, powder, or in liquid form.

In some cases, this drug is suitable and used to supply an adult with the following:

- from about 4 mg to about 7.5 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- from about 650 mg to about 1000 mg of paracetamol.

In some cases, this drug is suitable and used to supply an adult with the following:

- approximately 5 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 1000 mg of paracetamol.

In some cases, this drug is suitable and used to supply an adult with the following:

- approximately 6 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 1000 mg of paracetamol.

In some cases, this drug is suitable and used to supply an adult with the following:

- approximately 6 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 650 mg of paracetamol.

In some cases, this drug is suitable and used to supply an adult with the following:

- approximately 6 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 500 mg of paracetamol.

In another aspect, the invention provides a method for treating upper respiratory tract congestion due to swelling of mucous membranes in adults, comprising administering to a person or taking a combination drug containing phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine) and paracetamol, the person receiving or accepts:

- from about 4 mg to about 8 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- from about 500 mg to about 1000 mg of paracetamol.

In some cases, a person receives or accepts:

- from about 4 mg to about 7.5 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- from about 650 mg to about 1000 mg of paracetamol.

In some cases, a person receives or accepts:

- from about 5.8 mg to about 8 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- from about 500 mg to about 650 mg of paracetamol.

In some cases, a person receives or accepts:

- approximately 5 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 1000 mg of paracetamol.

In some cases, a person receives or accepts:

- approximately 6 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 1000 mg of paracetamol.

In some cases, a person receives or accepts:

- approximately 6 mg of phenylephrine hydrochloride (or an equivalent amount of another pharmaceutically acceptable form of phenylephrine); and

- approximately 650 mg of paracetamol.

Preferably, all of the above medicines are intended for dosage or for use by adults 4 times a day or every 4-6 hours.

Advantageously, the above-described medicaments and methods relate to adult use in a dosage of not more than 4 doses per day.

In some embodiments of the invention, the medicament or method may also include ibuprofen, for example, in an amount of about 300 mg per dose (for example, about 150 mg per tablet).

Alternative forms of phenylephrine may include, but are not limited to, citrates, maleates, and tannates.

In some embodiments of the invention, the medicament may be in powder form, for example, may be contained in a sachet, such that all or any of the aforementioned dosage amounts can be prepared by admixing the powder with water.

References in this document to "adults" should be understood as referring to persons aged 12 years or older, or to persons weighing 50 kg or more, preferably 60 kg or more, and most preferably 70 kg or more.

References in this document to paracetamol should be understood as encompassing all pharmaceutically acceptable therapeutic forms thereof. The indicated weight amounts must be adjusted in accordance with forms containing different amounts of paracetamol per se.

BLUEPRINTS

Figure 1 is a graph illustrating the enhanced absorption of phenylephrine hydrochloride when taken in combination with paracetamol.

Figure 2 shows the linear logarithmic dependence of the data from Figure 1.

Figure 3 is a graph illustrating enhanced absorption of phenylephrine hydrochloride when taken in combination with paracetamol.

Figure 4 shows the linear logarithmic dependence of the data from Figure 3.

5 is a graph of clinical trial data showing that a combination of 5 mg phenylephrine hydrochloride and 1000 mg paracetamol is comparable to 10 mg phenylephrine hydrochloride without additives.

DESCRIPTION OF THE INVENTION

Some preferred forms of the present invention will be illustrated by examples. You must understand that these examples should not be construed as limiting the scope of this invention, but serve only as an illustration of possible options for its implementation.

In preferred embodiments, the present invention is carried out in the form of a combined oral drug containing key painkiller Paracetamol and decongestant Phenylephrine hydrochloride. This medication is intended for the treatment of congestion of the upper respiratory tract due to swelling of the mucous membranes in adults caused, for example, by a common cold. In particular, this medication may be in the form of tablets or capsules, each of which contains:

- 500 mg paracetamol + 2.5 mg phenylephrine hydrochloride; or

- 325 mg paracetamol + 3 mg phenylephrine hydrochloride.

The tablets are intended for adults to take two pieces at a time every 4-6 hours or four times a day, to supply at each dose with the following amount of substances:

- 1000 mg paracetamol + 5 mg phenylephrine hydrochloride; or

- 650 mg paracetamol + 6 mg phenylephrine hydrochloride.

In other embodiments of the invention, the dosage amounts described in the previous paragraph are formulated as one tablet or capsule, for adults to take one such tablet or capsule at a time, every 4-6 hours or four times a day, wherein such a tablet or capsule contains:

- 500 mg of paracetamol + 6.25 mg of phenylephrine hydrochloride.

It was unexpectedly discovered that if paracetamol is administered together with low doses of phenylephrine hydrochloride, the absorption of phenylephrine hydrochloride into the bloodstream is synergistically and substantially increased. Although the mechanism of this process is not yet understood, it is believed that this improved absorption is the result of metabolic competition between paracetamol and phenylephrine hydrochloride in the stomach and small intestine. In the usual intake of phenylephrine, a significant amount is lost as a result of metabolic processes in the stomach and small intestine (presystemic metabolism). Competition is thought to lower this effect and allow more phenylephrine to enter the bloodstream. It was determined that when taking a dose of 5 mg phenylephrine hydrochloride + 1000 mg paracetamol, at least many organisms in adults absorb about the same amount of therapeutically significant phenylephrine hydrochloride as when taking 10 mg phenylephrine hydrochloride without additives.

It was determined that at lower doses of paracetamol, such as 500 mg, the effect is still significant, but already reduced. It was found that at a dosage of 6.25 mg of phenylephrine hydrochloride + 500 mg of paracetamol, the adult body absorbs approximately the same therapeutically significant phenylephrine hydrochloride as in the case of a dose of 10 mg of phenylephrine hydrochloride without additives.

This invention allows to create product formulations with a lower content of phenylephrine hydrochloride without losing its therapeutic efficacy. The advantage is that patients are at a lower risk of side effects. In the case of phenylephrine hydrochloride, such effects include exacerbation of latent hypertension, exacerbation of latent prostatic hyperplasia, relapse of symptoms of hyperemia, increased risk of seizures, indigestion, abdominal cramps and vomiting. This seems to be important, as it has been shown previously that with increasing doses of phenylephrine hydrochloride the likelihood of undesirable side effects increases significantly (Cohen BM (1972) Clinical and Physiologic Significance of Drug-Induced Changes in Nasal Flow / Resistance. Eur J Clin Pharmacol, 5 : 81-86).

Dose of Phenylephrine HCl Incidence of side effects 10 mg 12.5% 15 mg 43.8% 25 mg 81.3%

Since the authors found that taking phenylephrine in combination with paracetamol unexpectedly causes an effective increase in the amount of phenylephrine in the bloodstream, it is suggested that a combined dose of 10 mg of phenylephrine can cause unwanted side effects in an amount commensurate with a significantly higher dose. A dose of 10 mg of phenylephrine when taken with 500-1000 mg of paracetamol presumably corresponds to a dose of 16-20 mg of pure phenylephrine hydrochloride. As indicated in the table above, phenylephrine hydrochloride at this dosage level causes side effects at a frequency of approximately 43.8-81.3% compared to 12.5% for a dosage of 10 mg. Thus, this invention allows the creation of combined formulations of phenylephrine with paracetamol with a reduced risk of undesirable side effects without compromising the therapeutic effect of phenylephrine.

In preferred forms, tablets or capsules, if necessary, include inactive ingredients, for example binders, colorants, coatings, etc. Examples of commonly used inactive tablet manufacturing ingredients include corn starch, gelatin starch, microcrystalline cellulose, micronized stearic acid, magnesium stearate, sodium metabisulfite, disodium edetate, and purified water. These ingredients and methods for incorporating them into tablets or capsules are well known to those skilled in the art.

If the drug is in the form of tablets, then they are preferably presented in the form of a package, for example a blister pack. Such a package may contain an even number of tablets and instructions for taking 2 of them with a frequency of up to 4 times a day, or 2 tablets no more than every 4-6 hours. In some embodiments of the invention, the tablets may be loosely packaged in a bottle and provided with similar instructions.

In another embodiment of the invention, the medicament is in the form of a syrup for use by patients having difficulty swallowing tablets or capsules. Methods for the production of syrups are well known to specialists in this field and can be easily implemented in practice. The syrup is contained in a bottle, vial or similar container and is made in a manner suitable for delivery from about 4 mg to about 7.5 mg (most preferably about 5 mg) phenylephrine hydrochloride and from about 650 mg to about 1000 mg (most preferably about 650 mg or approximately 1000 mg) of paracetamol at a time, up to 4 times a day.

Example 1

Tablets intended for adults (2 tablets at a time) can be formulated according to the table below (weight amounts are given for one tablet).

500 mg paracetamol + 2.5 mg phenylephrine hydrochloride

Component Amount per tablet (mg) Dry mix Paracetamol 500.00 Phenylephrine hydrochloride 2,50 Gelatinized starch 20,832 Granulation Corn starch 34.00 Sodium metabisulfite 0.585 Disodium edetate 0,0571 Quinoline Yellow Supra 0.0285 Purified water * in sufficient quantity Grease Microcrystalline Cellulose (Microcel pH 102) 20.00 Magnesium stearate 5.00 Stearic acid (micronized) 2.00 * Purified water is not present in the final product.

Example 2

Tablets intended for adults (2 tablets at a time) can be formulated according to the table below (weight amounts are given for one tablet).

500 mg paracetamol + 3 mg phenylephrine hydrochloride

Component Amount per tablet (mg) Dry mix Paracetamol 500.00 Phenylephrine hydrochloride 3.00 Gelatinized starch 20,332 Granulation Corn starch 34.00 Sodium metabisulfite 0.585 Disodium edetate 0,0571 Quinoline Yellow Supra 0.0285 Purified water * in sufficient quantity Grease Microcrystalline Cellulose (Microcel pH 102) 20.00 mg Magnesium stearate 5.00 Stearic acid (micronized) 2.00 * Purified water is not present in the final product.

Example 3

Tablets intended for adults (2 tablets at a time) can be formulated according to the table below (weight amounts are given for one tablet).

325 mg paracetamol + 3 mg phenylephrine hydrochloride

Component Quantity per tablet (mg) Dry mix Paracetamol 325 Phenylephrine hydrochloride 3.00 Gelatinized starch 13.47 Granulation Corn starch 22.1 Sodium metabisulfite 0.38 Disodium edetate 0,0571 Quinoline Yellow Supra 0.0285 Purified water * in sufficient quantity Grease Microcrystalline Cellulose (Microcel pH 102) 13.00 Magnesium stearate 3.25 Stearic acid (micronized) 1.30 * Purified water is not present in the final product.

Example 4

Tablets intended for adults (1 tablet at a time) can be formulated according to the table shown below (weight amounts are given for one tablet).

Component Amount per tablet (mg) Dry mix Paracetamol 500.00 Phenylephrine hydrochloride 6.25 Gelatinized starch 17,082 Granulation Corn starch 34.00 Sodium metabisulfite 0.585 Disodium edetate 0,0571 Quinoline Yellow Supra 0.0285 Purified water * in sufficient quantity Grease Microcrystalline Cellulose (Microcel pH 102) 20.00 Magnesium stearate 5.00 Stearic acid (micronized) 2.00 * Purified water is not present in the final product.

It should be noted that in examples 3 and 4, the amount of paracetamol is less than in examples 1 and 2. The reason for this is a higher content of phenylephrine hydrochloride.

CLINICAL RESEARCHES

To compare the absorption of phenylephrine, taken as the sole active ingredient, with the absorption of phenylephrine hydrochloride, taken in combination with paracetamol, a cross-sectional study was conducted with 28 adults. Study participants received:

- 10 mg of phenylephrine hydrochloride in tablet form (PE HCl without additives); or

- 10 mg phenylephrine hydrochloride + 1000 mg paracetamol + 300 mg ibuprofen in tablet form (Maxigesic ™ PE).

After taking the drugs, the amount of phenylephrine in the blood plasma was measured and the average value was fixed. These values are shown graphically in FIG. 1 and demonstrate that phenylephrine is significantly more available for therapeutic purposes if taken in combination with paracetamol.

A graphical representation of the results in a linear logarithmic form, as can be seen in FIG. 2, shows a simultaneous decrease in concentration at least between 2 and 6 hours, which means that the half-lives in both cases are similar, and the difference in duration of action is determined by higher system availability phenylephrine hydrochloride in the presence of paracetamol. This is consistent with a decrease in the presystemic metabolism of phenylephrine hydrochloride and an increase in the availability of phenylephrine in the bloodstream.

The study also included non-compartmental pharmacokinetic analysis and bioequivalence assessment using the Kinetica computer program. Average results (SD) and 90% confidence intervals are shown in the table below. The results indicate a higher bioavailability of phenylephrine hydrochloride when taken in combination with paracetamol (Table 1).

Table 1 Bioequivalence Study Results Tmax * (h) Cmax (pg / ml) AUC0n (h * pg / ml) AUCtot (h * pg / ml) Average value 10 mg phenylephrine hydrochloride + 1000 mg paracetamol + 300 mg ibuprofen (n = 28) 0.6 3220,1 2219.8 2311.4 10 mg phenylephrine hydrochloride (n = 28) 0.7 873.8 1019.7 1104.6 90% Confidence Intervals Maxigesic ™ PE / PE NC 260.5-423.7 188.6-242.7 179.2-233.0

Although Maxigesic ™ PE contains ibuprofen, based on the results of various clinical studies (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022113Orig1s000ClinPharmR.pdf), phenylephrine hydrochloride does not increase in the presence of ibuprofen. In this regard, a second cross-sectional study was conducted with 30 adult patients to compare the absorption of phenylephrine when it was taken with various doses of paracetamol without ibuprofen. Study participants received:

- 10 mg of phenylephrine hydrochloride in tablet form (Sudafed ™ PE Nasal Decongestant) together with 500 mg of paracetamol in tablet form (Panadol ™); or

- 10 mg of phenylephrine hydrochloride and 1000 mg of paracetamol in tablet form in the form of two tablets of 5 mg of phenylephrine hydrochloride and 500 mg of paracetamol (Sudafec ™ PE Sinus and Pain Relief).

After taking the drugs, the amount of phenylephrine in the blood plasma was measured and the average value was fixed. These values are depicted graphically in FIG. 3 together with phenylephrine hydrochloride data without additives from the first experiment. The results demonstrate that phenylephrine is significantly more available for therapeutic purposes if taken in combination with paracetamol in amounts of 500-1000 mg. A graphical representation of the results in a linear-logarithmic form, as can be seen in Figure 4, shows a simultaneous decrease in blood concentration, independent of the dose of paracetamol.

A comparison of the pharmacokinetic data of the two treatment groups, shown below (Table 2), demonstrates the effect of a dose of paracetamol on the interaction, with a ratio of approximately 80% for a low dose of paracetamol (500 mg) compared to a high dose (1000 mg). It is believed that the cause of this is the metabolic competition of paracetamol with phenylephrine during absorption through the intestinal wall. In other words, with less paracetamol, such as 500 mg, the interaction is also less than with a higher dose of 1000 mg. However, the above-described interaction of low doses of paracetamol is unexpected.

table 2 Pharmacokinetic results of patients of the second study Tmax * (h) Cmax (pg / ml) AUC0n (h * pg / ml) AUCtot (h * pg / ml) Mean value (SD) 10 mg phenylephrine hydrochloride (n = 30) +1000 mg paracetamol 0.5 2545.8 2088.5 2192.0 10 mg phenylephrine hydrochloride + 500 mg paracetamol (n = 30) 0.5 2077.2 1673.5 1779.8 Ratio Nd 81.5% 80.1% 81.1%

A number of patients who participated in the first study also participated in the second study [N = 14]. The pharmacokinetic results were very similar in both studies of phenylephrine, as can be seen from the table below (Table 3).

Table 3 Pharmacokinetic results of patients from the first and second studies Tmax * (h) Cmax (pg / ml) AUC0n (h * pg / ml) AUCtot (h * pg / ml) Mean value (SD) 10 mg phenylephrine hydrochloride + 1000 mg paracetamol (n = 14) 0.5 2271.0 2094.2 2197.3 10 mg phenylephrine hydrochloride + 1000 mg paracetamol + 300 mg ibuprofen (n = 14) 0.7 3047,0 2156.7 2245.8 Ratio Nd 134% 103% 102%

In a third cross-sectional study, 6 adult patients took either two Maxiclear ™ PE 2.5 tablets (500 mg paracetamol + 2.5 mg phenylephrine hydrochloride) to produce 1000 mg paracetamol + 5 mg phenylephrine hydrochloride, or one Sudafed ™ PE tablet (10 mg phenylephrine hydrochloride). It was found that in a combination of 5 mg, the dose of phenylephrine shows a concentration-time curve similar to the curve when taking 10 mg of phenylephrine without additives. Pharmacokinetic parameters are summarized in Table 4 below.

Table 4 Pharmacokinetic results (not converted values) of patients of the third study Tmax * (h) Cmax (pg / ml) AUC0n (h * pg / ml) AUCtot (h * pg / ml) Mean value (SD) 5 mg phenylephrine hydrochloride + 1000 mg paracetamol (n = 6) 0.8 1597.9 1598.7 1842.1 10 mg phenylephrine hydrochloride (n = 6) 0.7 1131.9 1705.2 1915.5 Ratio Nd 165.5 95.6 94.9

Assessing the effect of various doses of paracetamol on the absorption of phenylephrine hydrochloride in the body, measured by the area under the plasma concentration curve versus time (AUCtot), it can be noted that the ratio increased by 1.98-2.09 due to 1000 mg of paracetamol. The small observed difference is supposedly the result of slight differences in composition. For lower doses of paracetamol (500 mg), AUCtot increases 1.60 times. This corresponds to the presence of lower amounts of paracetamol competing with phenylephrine hydrochloride in the absorption process. Based on a linear relationship in the dose range of 500-1000 mg, an increase in AUCtot of phenylephrine hydrochloride for a 650 mg dose of paracetamol is estimated to be approximately 1.73 times.

Table 5 The effect of various doses of paracetamol on the absorption of phenylephrine [PE] Treatment [amount of paracetamol] AUCtot (h * pg / ml) Ratio Maxigesic ™ PE (1000 paracetamol + 5 mg phenylephrine hydrochloride + 300 mg ibuprofen) 2311.4 2.09 Sudafed ™ PE Sinus & Pain Relief (1000 mg paracetamol + 10 mg phenylephrine hydrochloride) 2192.0 1.98 Calculation for paracetamol 650 mg (650 mg paracetamol + 10 mg phenylephrine hydrochloride) 1.73 Panadol ™ + Sudafed ™ PE Nasal Decongestant (500 mg paracetamol + 10 mg phenylephrine hydrochloride) 1779.8 1,60 10 mg phenylephrine hydrochloride (without paracetamol) 1104.6 1.00

Figure 5 shows a graph according to the obtained clinical data, which shows that 2 tablets of 2.5 mg phenylephrine hydrochloride + 500 mg paracetamol (giving a total of 5 mg phenylephrine hydrochloride + 1000 mg paracetamol) are comparable to 10 mg of pure phenylephrine hydrochloride.

Although some embodiments of the present invention have been described by way of examples, it will be appreciated that modifications and improvements to the described embodiments may take place without departing from the scope of the claims presented below.

Claims (14)

1. The use of a combination of phenylephrine hydrochloride or phenylephrine, or another pharmaceutically acceptable salt of phenylephrine, which provide an equivalent concentration of phenylephrine in the blood, and paracetamol as an active ingredient with an excipient for the manufacture of a medicament for the treatment of congestion of the mucous membrane of the upper respiratory tract of an adult, in the following ratios components per standard dose:
a) 4-7.5 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine in combination with 950-1000 mg of paracetamol, or
b) 5-7.5 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine in combination with 600-700 mg of paracetamol, or
c) 6-8 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine in combination with 500-550 mg of paracetamol. 2. The use according to claim 1, where the medical product is characterized by proportions suitable and intended for an adult, with a combination of 5-6.5 mg of phenylephrine hydrochloride, or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine and 950-1000 mg of paracetamol. 3. The use according to claim 1, where the medical product is characterized by proportions suitable and intended for an adult, with a combination of 5-6.2 mg of phenylephrine hydrochloride, or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine and 950-1000 mg of paracetamol. 4. The use according to claim 1, where the medical product is characterized by proportions suitable and intended for an adult, with a combination of 5 mg of phenylephrine hydrochloride, or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine and 950-1000 mg of paracetamol. 5. The use according to claim 1, where the medical product is characterized by proportions suitable and intended for an adult, with a combination of 5.8-7.1 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine and 625-675 mg of paracetamol . 6. The use according to claim 1, where the medical product is characterized by proportions suitable and intended for an adult, with a combination of 5.8 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine and 625-675 mg of paracetamol. 7. The use according to claim 1, where the medical product is characterized by proportions suitable and intended for an adult, with a combination of 6.25-7.6 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine and 500 mg of paracetamol. 8. The use according to claim 1, where the medical product is characterized by proportions suitable and intended for an adult, with a combination of 6.25 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine, or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine and 500 mg of paracetamol. 9. The use according to claim 1, where the medical preparation of part a) or part b) is obtained in dosage units containing both of these active ingredients, sufficient for two dosage units to provide the doses mentioned in part a) or b). 10. The use according to claim 1, where the medical product of part c) is obtained in dosage units containing both active ingredients, sufficient for each dosage unit to provide the doses mentioned in part c). 11. The use according to any one of claims 2 to 6, wherein the medicament is prepared in dosage units containing both of these active ingredients, sufficient for the two dosage units to provide the doses mentioned in any of claims 2 to 6, respectively. 12. The use according to any one of claims 1 to 11, wherein the medicament is in the form of a tablet, capsule, powder, or liquid form. 13. A medicinal product for the treatment of nasal mucosa of the upper respiratory tract of an adult, characterized in that it is obtained according to the use according to any one of claims 1-12. 14. A method for the treatment of congestion of the upper respiratory tract due to swelling of the mucous membranes in an adult, comprising administering to a person, or otherwise taking, a person a medicine containing as active ingredients
a) 4-7.5 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine in combination with 950-1000 mg of paracetamol, or
b) 5-7.5 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine in combination with 600-700 mg of paracetamol, or
c) 6-8 mg of phenylephrine hydrochloride or an equivalent amount of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt of phenylephrine in combination with 500-550 mg of paracetamol
and filler
wherein the medication is administered or taken in accordance with options a), b) or c) for the dose of medicine used.

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