MXPA97006661A - Improvements in organic or related compositionswith - Google Patents

Abstract

The use of potassium bicarbonate for the preparation of a pourable liquid aqueous composition, comprising at least 8% w / v of sodium alginate, to be used as a pharmaceutical agent.

Description

IMPROVEMENTS IN ORGANIC COMPOSITIONS OR RELATED TO THESE FIELD OF THE INVENTION The invention relates to the preparation of pourable liquid compositions of sodium alginate and, more particularly, relates to the preparation of these compositions for the treatment of esophagitis, gastritis, dyspepsia or peptic ulceration or for use as sustained release compositions.

BACKGROUND OF THE INVENTION Reflux esophagitis occurs when small amounts of gastric juice, food and / or bile acids pass into the lower part of the esophagus and cause inflammation of the esophagus accompanied by pain, which may manifest in the form of heartburn. One way to solve the problem of reflux esophagitis has been to administer a preparation that, in contact with gastric acid, generates a gelatinous, carbonated floating foam or mass floating on the contents of the stomach. When reflux occurs, it is this mass that precedes the content of the stomach into the esophagus, thus protecting the mucosa against further irritation. Known preparations of this type include solid preparations in P1401 / 97MX forms powders or tablets containing alginic acid, sodium bicarbonate and antacid materials or liquid preparations containing sodium alginate, sodium bicarbonate and calcium carbonate, which are marketed under the names of GAVISCON (Registered Trade Mark). &Colman Products Ltd). In our British Patent No. 1524740 we describe these liquid preparations. GB 1524740 specifies that sodium bicarbonate is used as the effervescent agent to generate carbon dioxide upon contact with stomach acid, and other very similar liquid products also employ the sodium salt. Sodium bicarbonate, in general, is the salt of choice for many reasons, including its taste characteristics, its solubility and its general pharmaceutical acceptability. Other bicarbonates, for example potassium carbonate, have been avoided in the past due to their poor taste characteristics (brackish taste) and due to the possibility of generating cardiac problems at high doses. A current problem with liquid alginate products of the above type is the size of the dose to be taken (up to 20 ml four times daily). This results in large volumes of product that can not be loaded conveniently and that P1401 / 97MX require a lot of space in pharmacies, warehouses etc. Therefore, an object of this invention is to provide a more concentrated product that reduces in this way the corresponding dose volume. On the other hand, we have found that simply doubling the concentration of all ingredients in conventional sodium alginate compositions leads to compositions that are too thick to be dispensed from a bottle and can even be so thick that they can not be swallowed without causing discomfort . On the other hand, we have found that by reducing sodium bicarbonate concentrations in these products the initial viscosity will be reduced to seemingly acceptable levels at which pouring of the composition can be achieved. However, if the bicarbonate concentrations are reduced too much, there will be an inadequate production of carbon dioxide in the stomach, which leads to an inadequate formation of the floating mass. We have also found that compositions having high concentrations of sodium alginate and low concentrations of sodium bicarbonate have an additional serious defect. Its pouring properties are lost if the storage temperature is too low.

P1401 / 97MX Specifically, if these compositions are stored at less than 5 ° C for 48 hours or more, they will remain too thick to be poured, even after they have been restored to room temperature and vigorously stirred. Temperatures of 5 ° C or less usually occur when commercial products are stored for long periods in warehouses or are transported over long distances. We have unexpectedly found that by using potassium bicarbonate in the above compositions these thickening problems are solved.

OBJECTIVES AND ADVANTAGES OF THE INVENTION According to the invention, the use of potassium bicarbonate is provided for the preparation of an aqueous composition in a pourable liquid state, comprising at least 8% w / w of sodium alginate, to be used as a pharmaceutical composition. These aqueous compositions in the liquid state that can be poured, which is obtained by the method of the invention, can be poured at room temperature and further this property is restored upon returning to room temperature after prolonged storage at less than 5 ° C for six months. weeks or more (although reasonable vigorous agitation may be required). P1401 / 97MX By "can be poured" we mean that the composition of the invention will flow uniformly at room temperature (possibly after reasonable vigorous stirring) so that a dose, for example 5 ml, can be measured with reasonable precision . For example, doses as low as 5 ml can be reproduced from screw cap bottles having 1.5 cm mouth diameters, or for collapsible plastic bottles having dispensing nozzles as small as 5 mm in diameter. The compositions of the invention, in particular those corresponding to the preferred embodiments, are in the liquid state, or else they pass into the liquid state upon vigorous stirring, even after prolonged storage at low temperatures. While the simple numerical viscosity is not an accurate prediction of the pouring capacity of the compositions of the invention, a coarse guide is that compositions having a viscosity of less than 3500 mPa.s are preferred and, more preferably, those which have a viscosity less than 2000 mPa.s. For the purpose of this coarse test the samples should be vigorously shaken before the test and the viscosity should be measured at a shear rate of lODs "1 in a hook and bowl viscometer." Alternatively, to stimulate the P1401 / 97MX vigorous agitation the samples can be sheared to 50Ds_1 in a viscometer before the viscosity measurement. Sodium alginate mainly comprises the sodium salt of alginic acid which is a mixture of polyuronic acids composed of D-mannuronic and L-guluronic acid residues. They can be obtained from algae that belong to the Phaeophycae family. Preferably, the low viscosity sodium alginate is used to prepare the compositions according to the invention. There are grades of sodium alginate for which the viscosity of an aqueous solution at 10% w / v, when determined in a Brookfield RVT viscometer using spindle number 3 at 20 r.p.m. at 20 ° C, it is within the range of 200 to 1500 mPa.s. An example of a commercial grade low viscosity sodium alginate is Protanal LFR 5/60 (Pronova Biopol). Preferably, sodium alginate has a high content of guluronic acid. The content of guluronic acid is expressed as gel firmness (G). Sodium alginate with high degrees of guluronic acid preferably has gel strengths of at least 10G. The concentration of sodium alginate in the compositions produced according to the invention is superior to conventional compositions, ie, by P1401 / 97MX at least 8% p / p. Preferably, the concentration is from 8 to 14% w / v, more preferably from 9 to 14% w / v, even more preferably from 10 to 13% w / v and still more preferably from 10 to 12% p / v. The concentration of potassium bicarbonate in compositions according to the invention is preferably from 0.1 to 5% w / v, more preferably from 0.5 to 5% w / v, and still more preferably from 1 to 3% w / v and more preferably from 1.5 to 3% w / v. The compositions which are prepared according to the invention can be used in the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulceration. They can also be used as carriers of other active ingredients and thus act in a sustained release composition or in compositions that specifically administer the active agents to the stomach (administration to a target site). further, according to the invention, there is provided a method for treating reflux esophagitis, gastritis, dyspepsia or peptic ulceration comprising the administration of an orally effective amount of an aqueous composition in a liquid, pourable state, comprising: a) 9 a 14% w / v of low viscosity sodium alginate; b) 0.1 to 5% w / v of potassium bicarbonate. P1401 / 97MX In addition, according to the invention, there is provided a pharmaceutical composition for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulceration or for use as a targeted or sustained release composition, in the form of an aqueous liquid pourable, comprising: a) 9 to 14 p / v of low viscosity sodium alginate; b) 0.1 to 5 p / v of potassium bicarbonate. The compositions of the invention preferably also comprise a suspending agent. Suitable suspending agents include carrageenans, hypromellose, tragacanth, pectin, pre-gelatinized potato cotton, sodium starch glycolate, carbomer and mixtures thereof. Carbomer is a high molecular weight synthetic polymer of acrylic acid crosslinked with either allylesters of sucrose or with pentaerythritol. Commercial grade carbomers include Carbopol 934P or Carbopol 974P (BF Goodrich). For use in liquid products, carbomers should be used after they have been predispersed in water. The neutralizing agent is sodium hydroxide. The carbomer concentration is given as the total amount of material used before neutralization. The selection of the suspension agent and its P1401 / 97MX concentration will depend on the amount and degree of the sodium alginate used in the compositions and the amount and type of additional insoluble ingredients that are employed. Preferably, the suspending agent is a carbomer. The preferred concentration of the suspending agent is 0.1 to 1% w / v, more preferably 0.1 to 0.5% w / v. The compositions of the present invention preferably comprise a source of divalent or trivalent metal ions to strengthen the floating mass formed in the stomach. These metal ions are preferably obtained when the compositions reach the stomach but should not be available beforehand, otherwise the compositions will gel well in advance. Suitable metal ions are aluminum ions and, preferably, calcium ions. More preferably, the compositions comprise calcium carbonate. The compositions of the present invention preferably also comprise from 0.1 to 5% w / v of calcium ions, more preferably from 0.5 to 3% w / v of calcium carbonate. Also, according to the invention, a pharmaceutical composition for the treatment of reflux esophagitis, gastritis, dyspepsia is provided P1401 / 97MX or peptic ulceration or for use as an aqueous composition of directed administration or sustained release, in liquid, pourable state, comprising: a) from 8 to 14 p / v of low viscosity sodium alginate; b) from 0.1 to 5 p / v of potassium bicarbonate; c) from 0.1 to 1% w / v of carbomer, neutralized with sodium hydroxide; and d) from 0 to 5% w / v, preferably from 0.5 to 5% w / v calcium carbonate. The compositions of the present invention, preferably, practically do not comprise sources of sodium ions other than that provided by sodium alginate and sodium hydroxide which is used to neutralize the carbomer. More preferably, sodium bicarbonate is not added during the manufacture of the compositions of the invention. The compositions of the present invention may further comprise preservatives to prevent contamination and subsequent spoilage by microorganisms. Examples of suitable preservatives are methyl, ethyl, propyl and butyl para-hydroxybenzoate and their salts, which are preferably used in combination, for example, with methyl and propyl or ethyl and butyl. The preferred concentrations of the preservatives are from 0.01 to 0.5% w / v. P1401 / 97MX The compositions of the present invention may also include one or more of the following ingredients, colorants, sweeteners, flavors or agents for pH adjustment. When the compositions of the present invention are intended to be used as sustained release compositions they will also contain active ingredients suitable for sustained administration in the stomach. When the compositions of the present invention are intended to be used as directed delivery compositions they will also contain active ingredients suitable for specific administration to the stomach, for example antimicrobial agents. The compositions of the invention can be prepared by any conventional manufacturing process for compositions of this type. Preferably the compositions are prepared for the following processes. 1) Dissolve the bicarbonate of potassium in approximately 60% of water to be used in the composition and mix any of the preservatives, sweeteners and crosslinking aids (if used) 2) Add the sodium alginate and stir until dissolved. P1401 / 97MX 3) Add the suspension agent (if used). If the suspension agent is carbomer, it must be previously neutralized with sodium hydroxide in approximately 30% of water to be used in the compositions. 4) Add any flavor or coloring agent and adjust the volume. The process of preference is carried out at a temperature of about 20 to 25 ° C. The invention will be described below in relation to the following examples.

Use 1 Sodium Alginate LFR 5/60 100 g (Pronova Biopol) Potassium bicarbonate 20 g Calcium carbonate 20 g Carbomer (Carbopol 974P) 1 g Sodium hydroxide 0.3 g Ethyl parahydroxybenzoate 2 g Sodium butyl parahydroxybenzoate 0.2 g Saccharin of sodium 2 g Flavor 2 g Deionized water for 1 liter P1401 / 97MX The carbomer was dispersed in 300 ml of deionized water in a first vessel and neutralized with sodium hydroxide. In a second vessel, potassium bicarbonate, calcium carbonate, preservatives and saccharin were mixed with 600 ml of deionized water. The sodium alginate was added to the second vessel and stirred until completely dissolved. The contents of the second container were added to the contents of the first container and stirred until completely dispersed. The flavor was added and the volume adjusted to 1 liter by the addition of more deionized water. The mixture was stirred until completely dispersed. 97MX Examples 2 to 12 The following Examples were all produced by the method of Example 1.

Sodium alginate 5/60 LFR (Pronova Biopol) 100 g 100 g 100 g 100 g 100 g Potassium bicarbonate 20 g 31 g 31 g 31 g 31 g Calcium carbonate 20 g 32 g 32 g 32 g 32 g Carbomer (Carbopol 974P) 2 g 2 g 4 g 6 g l g Sodium hydroxide 0.7 g 0.7 g 1.4 g 2.1 g 0.3 g Ethyl parahydroxybenzoate 2 g 2 g 2 g 2 g 2 g Butyl sodium parahydroxybenzoate 0.2 g 0.2 g 0.2 g 0.2 g 0.2 g Sodium saccharin 2 g 2 g 2 g 2 g 2 g Flavor 2 g 2 g 2 g 2 g 2 g Deionized water for l l l 1 liter liter liter liter liter P1401 / 97MX Sodium Alginate LFR 5/60 (Pronova Biopol) 100 g 100 g 100 g Potassium bicarbonate 20 g 10 g 25 g Calcium carbonate 32 g 32 g 32 g Carbomer (Carbopol 974P) 2 g 2 g 2 g Sodium hydroxide 0.7 g 0.7 g 0.7 g Ethyl parahydroxybenzoate 2 g 2 g 2 g Butyl parahydroxybenzoate sodium 0.2 g 0.2 g 0.2 g Sodium saccharin 2 g 2 g 2 g Taste 2 g 2 g 2 g Deionized water for 1 liter 1 liter 1 liter 11 12 Sodium alginate 5/60 LFR (Pronova Biopol) 100 g 100 g 100 g Potassium bicarbonate 31 g 31 g 31 g Calcium carbonate 16 g 8 g 24 g Carbomer (Carbopol 974P) 1 g 1 g 1 g Sodium hydroxide 0.3 g 0.3 g 0.3 g Ethyl parahydroxybenzoate 2 g 2 g 2 g Butyl parahydroxybenzoate sodium 0.2 g 0.2 g 0.2 g Sodium saccharin 2 g 2 g 2 g Taste 2 g 2 g 2 g Deionized water for 1 liter l liter 1 liter P1401 / 97MX Examples 2 to 12 can be repeated using 8 or 12% w / v of sodium alginate instead of 10%. Examples 2 to 12 can be further repeated using 0.5, 4 or 5% w / v of potassium bicarbonate. All of Examples 1 to 12 have the ability to be stored for at least 48 hours below 4 ° C and, in the case that a gel is formed, the composition can be poured at room temperature by reasonable agitation.

Examples 13 to 24 1.i 14 15 16 Sodium alginate LFR 100 g 80 g 100 g 100 g 5/60 (Pronova Biopol) Potassium bicarbonate 20 g 20 g 101 g 15 g Calcium carbonate 20 g 20 g 20 g 20 g Aluminum hydroxide Carbomer (Carbopol 974P) 4 g 4 g 4 g 4 g Sodium hydroxide 1.4 g 1.4 g 1.4 g 1.4 g Parahydroxybenzoate 2 g 2 g 2 g g ethyl Butyl parahydroxybenzoate 0.22 g 0.22 g 0.22 g 0.22 g sodium sodium saccharin l g l g l g l g Flavor 0.7 g 0.7 g 0.7 g 0.7 g Deionized water for 1 liter 1 liter 1 liter 1 liter P1401 / 97MX 17 18 19 20 Sodium alginate 5/60 LFR (Pronova Biopol) 100 g 80 g 100 g 100 g Potassium bicarbonate 20 g 20 g 101 g 15 g Calcium carbonate - - 20 g 20 g Aluminum hydroxide - 20 g Carbomer (Carbopol 974P) 4 g 4 g 4 g Sodium hydroxide 1.4 g 1.4 g 1.4 g Ethyl parahydroxybenzoate 2 g 2 g 2 g 2 g Butyl parahydroxybenzoate 0.22 g 0.22 g 0.55 g 0.22 g Sodium saccharine l g l g l g l g Flavor 0.7 g 0.7 g 0.7 g 0.7 g Deionized water for 1 liter 1 liter 1 liter 1 liter P1401 / 97MX 21 22 23 24 Sodium alginate 5/60 LFR (Pronova Biopol) 120 g 130 g 100 g 100 g Potassium bicarbonate 20 g 20 g 5 g 50 g Calcium carbonate - - 20 g 20 g Aluminum hydroxide - - Carbomer (Carbopol 974P) 4 g 4 g 4 g 4 g Sodium hydroxide 1.4 g 1.4 g 1.4 g 1.4 g Ethyl parahydroxybenzoate 2 g 2 g 2 g 2 g Butyl parahydroxybenzoate 0.22 g 0.22 g 0.55 g 0.22 g Sodium saccharine l g l g l g l g Flavor 0.7 g 0.7 g 0.7 g 0.7 g Deionized water for 1 liter l liter l liter 1 liter Each of Examples 13 to 24 were made by the general method of Example 1 (taking into account the necessary changes for the differences between the various formulas). Samples of each of Examples 13 to 24 are P1401 / 97MX stored at 4 ° C for 3 weeks and it was found that all could be easily poured after warming to room temperature and stirring.

P1401 / 97MX

Claims (8)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property; The use of potassium bicarbonate for the preparation of a liquid, pourable, aqueous composition comprising at least 8% w / v of sodium alginate to be used as a pharmaceutical agent.
2. 2. The use according to claim 1, wherein the concentration of the potassium bicarbonate is from 0.1 to 5% w / v.
3. 3. A composition for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulceration or for use as a directed or sustained release composition in the form of a pourable aqueous liquid, comprising: a) from 8 to 14 p / v of low viscosity sodium alginate; b) from 0.1 to 5 p / v of potassium bicarbonate
4. 4. A pharmaceutical composition according to claim 1, containing a suspension agent selected from carrageenans, hypromellose, tragacanth, pectin, pre-gelatinized potato cotton, starch glycolate, sodium, carbomer and mixtures thereof.
5. 5. A pharmaceutical composition according to claim 3 or 4, which contains an ion source P1401 / 97MX divalent or trivalent metal to make more resistant the floating mass that forms in the stomach.
6. 6. A method for treating reflux esophagitis, gastritis, dyspepsia or peptic ulceration, comprising administering an orally effective amount of a pourable liquid aqueous composition, comprising: a) 8 to 14% w / v of low viscosity sodium alginate; b) 0.1 to 5% w / v of potassium bicarbonate.
7. 7. A pharmaceutical composition for the treatment of reflux esophagitis, gastritis, dyspepsia or peptic ulceration or for use as a targeted or sustained release composition in the form of a pourable aqueous liquid, comprising: a) from 8 to 14% p / v of low viscosity sodium alginate; b) from 0.1 to 5% w / v of potassium bicarbonate; c) from 0.1 to 1% w / v of carbomer, neutralized with sodium hydroxide; and d) from 0 to 5% w / v, preferably from 0.5 to 5% w / v calcium carbonate.
8. 8. A pharmaceutical composition, substantially as described herein, in relation to any of the Examples. . The use of potassium bicarbonate substantially as described in relation to any of the examples. P1401 / 97MX