RU2506947C2 - Prolonged release tablet containing theobromin - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention refers to a prolonged release tablet containing theobromine and comprising a prolonged release layer and a fast release layer, wherein the prolonged release layer consists of 40-60 wt % of theobromine as an active ingredient and 14-19 wt % of a prolonged release base consisting of polyethylene oxide and hydroxypropyl methylcellulose, and the fast release layer consists of 10-30 wt % of theobromine as an active ingredient and 0.5-2 wt % of an aerating agent consisting of one or more ingredients specified in croscarmellose sodium, crospovidone and starch glycolate sodium salt.

EFFECT: prolonged release tablet according to the present invention effectively suppresses various types of cough symptoms if taken only once a day.

4 cl, 2 dwg, 4 tbl

Description

Technical field

The present invention relates to a sustained release tablet containing theobromine. In particular, the present invention relates to a sustained release tablet comprising theobromine, comprising a sustained release layer and a quick release layer, wherein the sustained release layer consists of 40-60 wt.% Of theobromine as an active ingredient and 14-19 wt.% Of a sustained release base consisting of polyethylene oxide and hydroxypropyl methylcellulose, and the quick release layer consists of 10-30 wt.% theobromine as an active ingredient and 0.5-2 wt.% baking powder yaschego of one or more components selected from sodium croscarmellose, crospovidone and sodium starch glycolate. The sustained release tablet of the present invention effectively suppresses various types of cough symptoms when taken only once a day.

State of the art

It is a known fact that cough is one of the common defense mechanisms in humans in the organisms of healthy individuals. However, coughing, which is usually caused by various diseases, significantly affects the quality of life. In this regard, the popularity of cough suppressants, such as codeine (drug) and dextromethorphan, is increasing. However, such cough suppressant ingredients affect the central nervous system, causing various side effects.

Theobromine is able to calm the cough due to the pharmacological suppression of the cough-inducing vagus nerve excitation at the ends of the bronchioles or in the lung. Theobromine is one of the key components of cocoa and is a member of the family of methylxanthines alkaloids. However, unlike caffeine or theophylline, theobromine rarely excites the central system. In addition, unlike conventional cough narcotics, which have various types of side effects on the central nervous system, theobromine is a non-narcotic substance, acting only on peripheral nerves, rarely showing side effects in the central nervous system.

Thanks to such pharmacological beneficial effects, a number of studies with theobromine have been performed to date. For example, the medicinal effect of theobromine against cough was disclosed in detail in Korean Patent No. 10-2001-5642, January 15, 2001. According to this patent, the therapeutic index of theobromine is about four times higher than that of codeine, another powerful cough suppressant, and, in addition, with regard to side effects, it is registered as significantly safer than other types of cough suppressants.

In addition, Korean patent No. 10-2008-9994, January 30, 2008 discloses a composition for treating a cough based on theobromine. According to the results of a clinical trial using capsules made with therapeutic compositions containing theobromine, theobromine showed the effect of a significant reduction in cough symptoms, while rarely giving side effects. In particular, it was reported that theobromine reduced cough symptoms caused by the following diseases: asthma, postnasal drip, and gastroesophageal reflux.

However, theobromine capsules disclosed in patent No. 10-20080-9994, have the disadvantage that in order to effectively treat cough symptoms, these capsules must be taken more than twice a day due to the short release time of the drug. In particular, for patients who do not observe dosage intervals and are unable to take the medicine on time, effective blood concentrations are not maintained, which leads not only to failure to suppress symptoms, but also prolongs the treatment period as a whole.

As described above, commercially available theobromine dosage forms have disadvantages that force patients to take these drugs at least more than twice a day.

Description of the invention

Technical problem

A key problem to be solved by the present invention is the development of a sustained release tablet containing theobromine, which can maintain its immediate and prolonged blood concentrations as a result of taking it only once a day.

Technical solution

In order to solve the aforementioned problem, the sustained release tablet of the present invention is characterized in that it consists of an extended release layer and a quick release layer, wherein the extended release layer consists of 40-60 wt.% Of theobromine or its salts, 14-19 wt.% Of the layer prolonged release, consisting of polyethylene oxide and hydroxypropyl methylcellulose, 1-2 wt.% a binding agent and 0.5-1 wt.% slip modifier, and the quick release layer consists of 10-30 wt.% theobromy on or its salts, 0.5-2 wt.% baking powder, consisting of one or more components selected from croscarmellose sodium, crospovidone and sodium starch glycolate, 0.3-1.5 wt.% binding agent and 0.1 -0.5 wt.% Slip modifier.

The present invention can be characterized by the fact that the content of theobromine or its salts contained in the aforementioned extended release and quick release layers is 300 mg or 600 mg.

In addition, the aforementioned extended release layer is characterized in that it consists of 6-10 wt.% Polyethylene oxide with a molecular weight of 900,000 ~ 1,000,000 and 8-12 wt.% Hydroxypropyl methylcellulose with a viscosity of 4000 cP.

Finally, the aforementioned extended release and quick release layers are notable for the fact that they are a two-layer structure with an upper and lower layer, or a three-layer structure that has quick release layers in the upper and lower layers and a sustained release layer between them.

Beneficial effects

Theobromine-containing sustained release tablet of the present invention maintains effective concentrations of the ingredients in the blood for more than 24 hours due to the rapid release of the effective ingredients from the quick release layer, resulting in a quick initial effect after administration of the drug, in addition to the prolonged release effective ingredients from a sustained release layer. As a result, various types of cough symptoms can be effectively suppressed by simply taking the pill once a day.

A brief description of the graphic materials

Figure 1 is a graph showing a dissolution curve of sustained release tablets obtained in accordance with Examples No. 1-5 of the invention, and

Figure 2 is a graph showing a dissolution curve of sustained release tablets obtained in accordance with Examples No. 6-10 of the invention.

The best way of carrying out the invention

The present invention can be described in detail as follows.

Sustained-release tablets prepared in accordance with the present invention consist of a sustained-release layer and a quick-release layer, wherein the sustained-release layer consists of 40-60 wt.% Of theobromine or its salts, 14-19 wt.% Of the sustained-release base, 1- 2 wt.% Binding agent and 0.5-1 wt.% Slip modifier, and the quick release layer consists of theobromine or 10-30 wt.% Its salts, 0.5-2 wt.% Disintegrant, 0.3-1 , 5 wt.% A binder and 0.1-0.5 wt.% Slip modifier.

First of all, theobromine active ingredient may be theobromine free base or pharmaceutically acceptable sodium chloride. In addition, it is recommended that the tablet contains 300 mg or 600 mg (of the order of 65 to 75% by weight of the total weight of the sustained release tablet). Two tablets per day should be taken if the tablet contains more than 300 mg of theobromine, while only one tablet can be taken per day if the tablet contains more than 600 mg of theobromine.

If the proportion of the relative content of theobromine contained in the aforementioned extended release layer is less than 40 wt.% Or more than 60 wt.%, The released amounts of the active ingredients 12 hours after administration of the drug may be too large or too small, and if the relative content theobromine contained in the quick release layer is less than 10 wt.% or more than 30 wt.%, any desired release patterns may not be retained since the amount of The initially released active ingredients are too small or too large.

The aforementioned sustained release base, a key feature of this invention, consists of 14-19 wt.% Polyethylene oxide and hydroxypropyl methylcellulose. However, if the content of the aforementioned sustained release base is less than 14 wt.%, The desired sustained release function cannot be achieved since the release rate is too high. On the contrary, if the content is more than 18 wt.%, This base can be released from the body through defecation due to the properties of delayed loosening. For polyethylene oxide, Polyox ™ (purification according to National Formula (NF): WSR-1105 NF, Dow Company) with a molecular weight of 900,000 or Polyox ™ (purification according to NF: WSR N-12K NF) with molecular weight is recommended weighing 1,000,000. The use of hydroxypropyl methylcellulose with a viscosity of 4000 cP is also recommended.

In addition, the aforementioned baking powder consists of one or more components selected from croscarmellose sodium, crospovidone and sodium starch glycolate, and the recommended content is 0.5-2 wt.%. Although the content of the aforementioned disintegrant is not very significant from a technical point of view, the content of less than 0.5 wt.% Or more than 2 wt.% Can lead to undesirable consequences due to the too slow or too fast speed of the quick release layer.

In addition, the aforementioned sustained release and quick release layers contain binding agents and slip modifiers, respectively. You can use any of the commercially available binders or slip modifiers. As the binding agent, one or more components selected from hydroxypropyl methyl cellulose, copovidone, methyl cellulose and gelatin can be used; and as a slip modifier, one or more components selected from solid silicic anhydride, talc and magnesium stearate can be used. However, it is recommended that the aforementioned extended release layer contain 1-2 wt.% A bonding agent and 0.5-1 wt.% A slip modifier, and the quick release layer contains 0.3-1.5 wt.% A bonding agent and 0.1 -0.5 wt.% Slip modifier.

The above sustained release and quick release layers may also contain some excipients, such as D-mannitol, lactose, microcrystalline cellulose, and the like, and, if necessary, various dyes may also be contained. The content of the aforementioned diluents and dyes, if desired, can be adjusted accordingly.

Sustained release layer compositions and quick release layer compositions should be prepared using a wet process with the ratio of the components of the composition shown above in order to obtain theobromine extended release tablets according to the present invention, and then sustained release and quick release layering tablets the release should be prepared using a conventional tablet forming apparatus.

In this case, the aforementioned tablets can be prepared in the form of two-layer tablets with a layering layer of a prolonged release and a layer of quick release or in the form of three-layer tablets, the upper and lower layers of which are layers of quick release, and the layer of prolonged release is located between them.

Samples prepared in accordance with the present invention are as described below.

Examples

Theobromine (active agent) and microcrystalline cellulose are mixed with each other according to the proportions in the composition of the quick release layer described in detail in table 1 or table 3, as shown above, and hydroxypropyl cellulose is added to the mixture to carry out the wet granulation process, and then the granules are dried and a quick release composition is prepared after mixing with croscarmellose sodium and magnesium stearate.

Then, theobromine (active ingredient), microcrystalline cellulose and hydroxypropyl methyl cellulose are mixed with each other according to the proportions in the composition of the sustained release layer described in detail in table 1 or table 3, and a binder solution containing hydroxypropyl cellulose is added to the mixture to wet the process granulation, and then the granules are dried and a sustained release composition is prepared after mixing with polyethylene oxide and magnesium stearate.

Then, the quick release and sustained release compositions are formed using a conventional tablet forming apparatus. Moreover, in the cases corresponding to Examples No. 1-7, two-layer tablets should be formed, where the upper and lower layers consist of a quick release layer and a prolonged release layer, respectively; and in the cases corresponding to Examples No. 8-10, three-layer tablets should be obtained, the upper and lower layers of which are composed of quick release layers, where a sustained release layer is located between them. Then, the manufacture of sustained release tablets that can be used for oral administration should be completed by coating the tablets with the commonly used film coating base. Although the fabricated samples No. 8, 10, 3, 6, and 7 have only structural differences in layering, the quick release composition and the sustained release composition remain the same.

From Examples No. 1-10, theobromine content in Example No. 1 was 600 mg, while in Examples No. 2-10 it was 300 mg.

Disintegration Test

As for the sustained release tablets obtained in accordance with Examples No. 1-10, as shown above, disintegration tests were carried out in accordance with the "disintegration testing method" selected from the general testing methods described in the Korean Pharmacopoeia, and the test results are presented below in table 4. At this stage, several theobromine capsules currently commercially available (drug name: Anycough Capsule, AHN-GOOK PHARMA CO., LTD) were used as the Comparative Sample.

Table 4 p.p. Etc. No. 1 Etc. Number 2 Etc. Number 3 Etc. Number 4 Etc. Number 5 Etc. Number 6 Etc. Number 7 Etc. Number 8 Etc. Number 9 Etc. Number 10 Comparative sample Time 10 h 7 h 8 h 8 h 8 h 8 h 10 h 8 h 8 h 8 h less than 4 min 29 min 47 min 21 min 15 minutes 25 min 24min 29 min 18 min 29 min 27 min

As the test results in table 4 show, it was found that the extended release tablets obtained in accordance with this invention correspond to extended release tablets, showing a significantly longer loosening time than the Comparative Sample. In particular, Examples No. 8-10 are three-layer tablets made with the two-layer tablets used in Examples No. 3, 6 and 7, and do not show a significant quantitative change in the loosening time between the two groups, despite this structural difference.

Comparative Dissolution Testing

Comparative dissolution tests were performed on sustained release tablets made in accordance with Examples No. 1-10, as shown above, and the results are illustrated in graphs 1 and 2 in the appendix. An exit pH of 6.8 was used under stirring with a paddle stirrer at 50 rpm, using comparative dissolution testing in accordance with control standards for drugs.

As shown by the results of the comparative dissolution testing described above, sustained release tablets made in accordance with the present invention result in an increase in the release amount within 24 hours by providing a continuous release of the drug, while at the same time preventing a spasmodic release of the drug from time, where similar dissolution curves were detected regardless of structural differences (two-layer structure or three-layer ynaya structure). Such results demonstrate the fact that the concentration of active ingredients in the blood can remain for up to 24 hours inside the body.

Finally, sustained release tablets containing theobromine made in accordance with the present invention are able to produce a quick initial effect after taking the drug, while maintaining effective concentrations of the active ingredients in the blood for more than 24 hours due to the continuous release of the effective ingredients in the layers prolonged release.

In this regard, sustained release tablets made in accordance with the present invention are able to effectively suppress a wide range of cough symptoms when taken only once a day.

Claims (4)

1. A sustained release tablet containing theobromine, which consists of a sustained release layer and a quick release layer,
where the extended release layer consists of 40-60 wt.% of theobromine or its salts, 14-19 wt.% of a sustained release base consisting of polyethylene oxide and hydroxypropyl methylcellulose, 1-2 wt.% a binding agent and 0.5-1 wt.% slip modifier;
where the quick release layer consists of 10-30 wt.% theobromine or its salts, 0.5-2 wt.% disintegrant, consisting of one or more components selected from croscarmellose sodium, crospovidone and sodium starch glycolate, 0.3- 1.5 wt.% A binder and 0.1-0.5 wt.% Slip modifier. 2. The sustained release tablet according to claim 1, wherein the content of theobromine or its salts in the sustained release layer and in the rapid release layer total 300 mg or 600 mg. 3. A sustained release tablet according to claim 1 or 2, wherein the sustained release base comprises from 6 to 10 wt.% Polyethylene oxide with a molecular weight of 900,000-1000000 and from 8 to 12 wt.% Hydroxypropylmethyl cellulose with a viscosity of 4000 cP. 4. The sustained release tablet according to claim 1 or 2, wherein the extended release layer and the quick release layer are formed from two-layer structures layered in both up and down directions, or a three-layer structure that has upper and lower layers, which are quick layers release, and a sustained release layer is located between them.

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