Thermostable antacid suspension

 

The invention relates to thermostable antacid suspension capable of posteritati at a temperature in the range of 60-100oWith, including one or more neutralizing acid and carminative compounds in liquid water suspension containing as a suspending agent is hydroxyethyl cellulose. The advantage of suspensions is their quick action. 4 C. and 15 C.p. f-crystals, 3 tables.

The invention relates to a liquid antacid compositions and methods for their preparation. More specifically, the invention relates to thermostable liquid antacid and carminative drugs, containing suspendresume agents that pasteurization does not turn into a gel or do not interact with anti-acid salts of metals such compositions.

Description of the prior art gastric Antacid remedies are substances that neutralize or remove the acid from the stomach contents. Antacids are widely used in the treatment of various gastrointestinal disorders such as peptic ulcers and gastritis. Antacids are also used to relieve heartburn, reduce dyspepsia, acidity reflux esophagitis, etc. Clinical use

Currently used antacids receive from various inorganic salts, such as calcium carbonate, sodium bicarbonate, magnesium salts and aluminum salts. Magnesium hydroxide and aluminum hydroxide are the most potent salts of magnesium and aluminum, and they are often used in combination. In addition, also use magnesium oxide, magnesium carbonate, aluminum phosphate, magaldrate, magnesium trisilicate and aluminum sucrose sulfate (sukralfat).

Carminative drugs are tools, used as an auxiliary in the treatment of symptoms of flatulence, functional bloating and education-related gases postoperative pain.

Clinical use of such carminative medicines, such as simethicone, based on their protivovspenivayushchie properties. Silicone protivovspenivayushchie substance spread on the surface of the aqueous liquid, forms a film with low surface tension, thus causing the destruction of the bubbles of the foam. This leads to symptomatic relief of pain and disorders associated with the formation of gases.

Antacid and carminative preparations can be in liquid form in suspension and solid lekarstvennie and effectively dissolve and have greater ability to react with gastric acid to neutralize it, or the ability to reduce emissions. The main advantage of such liquid preparations is their quick action. However, the difficulty associated with the use of liquid drugs, as a rule, is the storage conditions and the final sterilization of packaged product. It is extremely important for the storage of these products is that they must be packaged in containers for storage so bactericidal pure as possible (i.e., permanently sterilized). Such sterilization can be done either (i) by adding chemicals such as sodium hypochlorite or hydrogen peroxide, to products in the process of packing (UK patent GB 1275885) or (ii) heat treatment (pasteurization) liquid antacid.

However, such sterilization methods have several disadvantages. The disadvantage of method (i) is the unpleasant taste of the resulting product, and that product needs to be packaged in bottles to decompose chemical substances, which depends on the initial added amount of these substances. The main problem of the method (ii) is the effect of heat on components of the composition. More specifically, the problem is the influence of increased temperature on suspendresume agents (smoca is what suspendresume agents have a tendency to gelation under the action of elevated temperatures that are within a temperature pasteurization of the product. The choice suspendida agents, moreover, is limited to substances that do not interact with metal ions. From commercially available suspendida agents most widely used hypromellose (receiver array), traditionally believed that it is the most suitable substance compatibility with antacids (metal ions), and also due to the fact that pasteurization can be carried out at not very high temperatures of 60-70oC.

However, pasteurization in this temperature range is far from ideal. Another problem is that only a limited amount of product you can skip through pictureswomen the device before it will be blocked receiver array formed gel. High temperature gelation is a well known phenomenon associated with a receiver array (see, for example, A. Hague et al. , Termogelation of Methylcellulose. Part II: effect of hydroxypropyi substituents. Carbohydrate Polymers 22 (1993) 175-186). Accordingly, high-temperature gelation of a suspending agent in the process of pasteurization restricts production is the provision of a liquid antacid compositions which can be pasteurized at a temperature in the range of 60-100oWith, without gelation or interaction with divalent and/or trivalent antacid salts of the metals contained in the composition.

BRIEF description of the INVENTION the Invention relates to thermostable liquid antacid and/or carminative drugs that can posteritati at a temperature of 60-100oWith, including one or more neutralizing the acid and/or carminative compounds in aqueous liquid suspensions containing hydroxyethyl cellulose as a suspending agent. It was found that when as a suspending agent for antacids and/or carminative suspensions using hydroxyethyl cellulose (NES), the obtained product has the following properties: (i) It is easily sterilized by pasteurization, without causing problems such as gelation suspending agent in the pasteurizer. It is not typical for other cellulosic resins, such as resin or a receiver array LDCs.

(ii) In the case when the antacid compositions containing aluminum, calcium or magnesium, NES does not interact with residual amounts of free multivalent metal ions such as cations Al3+, CA2+or MD

(iii) CARRIED by itself is not the biological cargo, as some natural gums, such as guar gum, gum acacia, tragakant, resin Robinia, etc.

The advantage of using BORE as suspendida substances in antacid and/or carminative suspensions (in particular those containing aluminum, magnesium or calcium antacid substances) makes it easy to implement the final sterilization of the product by means of pasteurization.

DETAILED description of the INVENTION the Invention relates in particular to a liquid antacid and/or carminative preparations comprising an effective amount of one or more neutralizing acid compounds and/or carminative compounds, hydroxyethylcellulose (NES) suspendresume agent and, optionally, one or more other pharmaceutically acceptable additives. Preferably the product contains 1.0 mg 50 mg/5 ml BORE a suspending agent.

Antacid compounds suitable for use as the active neutralizing acid compounds according to the invention are salts of aluminum, magnesium and calcium that are commonly used in liquid antacid components to use calcium carbonate in an amount of from 200 to 2000 mg per 5 ml, and magnesium carbonate, magnesium trisilicate, aluminum hydroxide and magnesium hydroxide, and mixtures thereof. The amount of antacid substances in the composition preferably is, for example, in the range of 5-35 wt./about. of the composition. Preference is given to using mixtures containing from about 5 to about 15 wt%./about. calcium carbonate and about 2-8% of magnesium carbonate or trisilikata magnesium. You can also use the gel-like aluminum hydroxide in an amount of from about 150 to about 800 mg per 5 ml Active neutralizing the acid compounds are usually used in the form of separate powders, preferably finely ground powders.

Alternative or in addition to neutralizing the acid to the compound of the composition may contain carminative connection, such as simethicone, as an active ingredient. Such carminative compounds are compounds that are used as auxiliary means for the treatment of symptoms of flatulence, functional bloating and postoperative pain associated with gas. In order to obtain a secure proprietary medicinal products intended for the treatment of symptoms, usually called "gases", including bloating, a feeling of pressure, parachutiste remedy for flatulence. Simethicone is often combined with other gastrointestinal means, such as antacids, antispasmodic or digestive enzymes. Preferably simethicone meets the definition of a United States Pharmacopeia (USPXXII), is a mixture of fully methylated linear siloxane polymers containing repeating units of the formula (-(CH3)2SiO-)n, stable trimethylsiloxy blocking links on the ends of the chain of the formula-(CH3)3SiO-), and silicon dioxide. Other organopolysiloxane protivovspenivayushchie substances known in the art and can also be used as the active ingredient of the present invention. Such organopolysiloxane protivovspenivayushchie substances are disclosed, for example, in U.S. patent 5458886, as well as in the documents referenced in this patent, all of them are included in this invention as a reference.

The number of simeticone or other organopolysiloxanes protivovspenivayushchie agent contained in the solid dosage form for oral administration, should be sufficient to provide a therapeutic dose to a patient suffering from gas or flatulence and svyazannyis dosage forms and usually does not exceed 500 mg/day. The scope of dosing may vary depending on the age and weight of the patient, and the severity of the symptoms.

Suspendisse agent is selected from polymers of hydroxyethyl cellulose (NES), known from the prior art. BORE is a water-soluble polymer derived from cellulose, which is non-ionic and therefore is not affected by being in solution cations, unlike other Jonny cellulating polymers. This quality makes it ideal for use with bivalent and/or trivalent cation antacid salts, which are traditionally used. BORE is obtained from cellulose by treatment with sodium hydroxide and interaction with ethylene oxide to introduce hydroksyetylowy groups to obtain hydroxyethylamide ether. Under certain reaction conditions it is possible to control the degree of substitution of hydroxyl groups. Solubility in water is achieved by increasing the degree of substitution. BORE is commercially available, with different types of viscosity and solubility, under the trade name NATROSOLRfrom Aqualon company, which is a branch of the company Hercules Incorporated, Wilminqton DE, or under the trade name TYLOSERfrom the company Hoechst Celanese in an amount of from 1 mg / 5 ml to about 100 mg per 5 ml, or about 0.02 wt%/about. up to about 2% wt./about. song.

The stabilizing component liquid antacid suspensions may also preferably contain a preservative, selected from any pharmaceutically acceptable preservative. Preferred are complex alkalemia esters by parahydroxybenzoic acid (parabens, such as butylparaben, methylparaben or propylparaben), and can be used separately or in combination. Usually parabens are used in a concentration of about 0.02 wt./about. Other preservatives include ethylenediaminetetraacetic acid, propyl-p-hydroxybenzoate, sodium benzoate or sorbic acid.

Mostly liquid antacid preparation may also contain antagonists histamine H2 receptor or other active substance, usually used in gastro-intestinal drugs. Antagonists histamine H2 receptor are substances that reduce acid secretion, and are effective in the treatment of many gastric disorders. The joint introduction of the antagonists histamine H2 receptor and antacid substances known, for example, from U.S. patent 5229137 and WO 92/00102. You can use any of the known antagonists histamine H2 receptor, for example zimet is from about 50 mg to about 150 mg of ranitidine, or from 10 mg to 40 mg of famotidine per unit dosage form (e.g., 5 ml). Usually the antagonist of histamine H2 receptor used in free base form or in the form of physiologically acceptable salts, such as cleaners containing hydrochloride salt in the case of ranitidine. The composition can be added and other active substances. For example, analgesics, substances against diarrhea or antispasmodic agents, and other substances for the treatment of gastro-intestinal tract in number, commonly used to treat gastrointestinal disorders.

Unit dosage forms of the composition according to the invention can be entered, for example, 1-4 times per day. The dose depends on the active substances, the condition to be treated, and the age and weight of the patient. Typical dosages comprise about 5-30 ml of a preparation containing a dose of antacid substances, selected to achieve the desired acid-neutralizing effect. A suitable dose of the calcium carbonate is in the range of 200 mg to 2.0,

Liquid compositions according to the invention are aqueous suspensions containing the active ingredients in a mixture with pharmaceutically acceptable excipients, typically present in aqueous suspensions, prednisne substances, such as esters sorbitan or lecithin, surface modifiers, aqueous or non-aqueous media, such as a solution of sorbitol, ethyl alcohol or refined vegetable oil, or thinners.

The composition may also contain fragrances, dyes and/or sweeteners, if desired. Suitable fragrances include fruit flavors, peppermint, liquorice or odorants used for chewing gum. As sweeteners can be used, for example, bulk podslushivala, such as sugars (like sucrose or fructose) or polyols (for example, ▫ maltitol, sorbitol) and/or intensive podslushivala, such as saccharin, aspartame or Acesulfame K.

In addition, the composition may contain buffer substances, such as three - or diepiriye buffers, such as triacetin, or other buffers or buffering salts, such as tartaric acid or citric acid.

Liquid antacid compositions according to the invention can be obtained by conventional methods well known in the pharmaceutical industry. For example, antacid substance and suspendisse agent can be mixed, if desired, with suitable excipients and dispersing in aqueous media.

the AET significant advantages in the manufacture of liquid antacid compositions requiring the use of a suspending agent, as the final sterilization of the product can be made by way of pasteurization without fear that the pasteurizer suspendisse the agent can move in the gel state. This is not typical of other cellulose resins, such as a receiver array or LDCs. Demonstrating the above, the results of the following example 1 shows that the composition according to the invention contains as a suspending agent CARRIED, demonstrates the increased flow velocity in the pasteurization process in comparison with the comparative composition containing as a suspending agent receiver array.

In order to further illustrate the present invention and its advantages the following are specific examples of its implementation, it should be understood that these examples are for illustrative purposes only and may not serve as limitations of the scope of the invention.

EXAMPLE 1 Comparison of thermal stability of the BORE and a receiver array, the recycling Process has been studied in industrial heat exchangers installation APV. The purpose of these studies was to compare the degree of blockage (thrombosis), observed in the heat exchanger when processing it antacid substances, susp is ethylcellulose (NES).

As a receiver array, and BORE are aqueous colloidal solutions of cellulose, which increase the viscosity of the liquid product. In table 1 (tables 1-3 are given in the end of the description) presents the formulations of the drugs used in this study. It should be noted that the viscosity at room temperature (RT) (Brookfield viscometer (Brookfield) 2, speed 12) of these compounds is the same (SDR 225). For this study used two load displacement of 500 Gal (2273 l). After processing both download homogenized at a pressure of 1600 F./inch2(112.5 kg/cm2prior to pasteurization.

Table 2 illustrates the reduced clogging of the heat exchanger when using the composition according to the invention using a BORE in comparison with equivalent composition using a receiver array. The product was recycled for 5 minutes, then trenirovki manually for 15 minutes at a speed of about 1.2 Gal. /min (5.4 l/min). After draining of the product was recycled for another 5 minutes and then was trenirovki within 15 minutes. This was repeated for 210 minutes. Throughout the process was controlled by changing the injection pressure and injection %. The increase in injection pressure and/or injection % palazzotti these studies. These results do not show any significant changes in these parameters for the composition CARRIED by the present invention, whereas the composition of the receiver array showed a significant increase in injection pressure and injection %. In General, studies show that when using the CARRIED composition did not observe any signs of clogging of pasteurizers.

As a result of change in the composition of antacid receiver array for CARRYING received a significant improvement of product yield to complete clogging of the heat exchanger.

EXAMPLE 2 a Composition containing a gel of aluminum hydroxide - mg/5 ml Gel Al(Oh)3(13% Al2O3) - 1538,5 Sorbitol (70%rest.) - 1000,0
Hydroxyethylcellulose - 15,0
Deionized water - 3023,5
Odorant - 20,0
Propylparaben NF - 2,0
Butylparaben NF - 2,0 - 5591,0
302,35 g of deionized water and 200 g 70% sorbitol solution were placed in a reaction vessel with a capacity of 1.5 liters, equipped with a mixing device IKA. In mixer at high speed mixing to the mixture water/sorbitol was added 3 g of hydroxyethyl cellulose. Mixing was continued until complete dissolution of hydroxyethyl cellulose. To the vessel was added 307,7 gel aluminum hydroxide, also at high speed mixed. Immediately po,4 g of butylparaben, 0.4 g of propyl paraben, 4.0 odorants, in the end added 302,35 g of deionized water.

The suspension is homogenized and pasteurizable in plastic bottles.

EXAMPLE 3
The composition containing the powder caso3and simethicone mg/5 ml
The powder caso3- 1000,0
Simethicone (30% emulsion) - 100,0
Sorbitol (70% solution) - 1000,0
Hydroxyethylcellulose - 15,0
Deionized water - 3461,0
Odorant - 20,0
Propylparaben NF - 2,0
Butylparaben NF - 2,0 - 5600,0
In a reactor with a capacity of 1.5 liters, equipped with a mixing device IKA, put 500.0 g of deionized water and 200 g of 70% solution of sorbitol. With high speed stirring was added a powder of caso3. After full dispersione caso3to the mixture was added 3 g of hydroxyethyl cellulose. Stirring is continued until complete dissolution of hydroxyethyl cellulose. Then in the reaction vessel at high speed stirring was added 20 g of the emulsion simeticone. Immediately after complete dispersion of simeticone emulsion were added the following ingredients in the order listed:
0.4 g of butylparaben, 0.4 g of propyl paraben, 4.0 g of odorants at the end was added 192,2 g of deionized water.

The suspension is homogenized and pasteurizable the
DASC - 400,0
Sorbitol (70% solution) - 1000,0
Hydroxyethylcellulose - 25,0
Deionized water - 3851,5
Odorant - 22,0
Sodium saccharin - 1,5 - 5300,0
In a reaction vessel with a capacity of 1.5 liters, equipped with a mixing device IKA, put 385,15 g of deionized water and 200 g of 70% solution of sorbitol. To a mixture of water/sorbitol with high speed stirring was added 5 g of hydroxyethyl cellulose. Stirring is continued until complete dissolution of hydroxyethyl cellulose. Also, under high speed stirring in the reaction vessel was added 80,0 g DASC. Immediately after complete dispersion DASC were added the following ingredients in the order listed:
4.4 g of odorants, and 0.3 g sodium saccharin, at the end I added 385,15 g of deionized water.

Then, the suspension is homogenized and pasteurizable in plastic bottles.

EXAMPLE 5
The composition containing simethicone mg/0.6 ml
Simethicone (30% emulsion) - 140,48
Microcrystalline cellulose and sodium CMC - 0,60
▫ Maltitol - 60,0
Hydroxyethylcellulose - 1,50
Deionized water - 418,54
Citric acid - 0,75
Sodium citrate - 0,30
Sodium benzoate is 0.60
Odorant - 1,20
Dye - 0,03 - 624,00
In the tank 2000 l was placed 792,0 kg deionized what do 2,839 kg BORE and continued stirring for another 5 minutes. In reservoir were added the following ingredients in the following order: citric acid (1.42 kg), sodium citrate (0,568 kg) ▫ maltitol (113,6 kg) and sodium benzoate (1,136 kg). Then added simeticone emulsion (266 kg) with thorough stirring. Immediately after complete dispersion of simeticone emulsion were added the following separately prepared mixture of 57 g of the dye and 1.2 kg of odorants, dispersed in 10 kg definitivno water. Immediately after adding the mixture in the tank was kept stirring for another 30 minutes

Then, the suspension is homogenized and pasteurizable in plastic bottles.


Claims

1. Thermostable liquid antacid drug that can posteritati at a temperature of from 60 to 100°C., comprising one or more compounds, neutralizing the acid in the aqueous liquid suspension containing hydroxyethylcellulose as a suspending agents, and optionally one or more pharmaceutically acceptable additives.

2. Liquid antacid drug under item 1, further comprising carminative drug.

3. Liquid antacid drug under item 1, comprising 200 mg to 2000 mg/5 ml neutralizing acid compounds and 1 mg - 100 mg/5 m is its acid compound selected from calcium carbonate, dihydroxyaluminum sodium carbonate, magnesium carbonate, trisilikata magnesium, aluminum hydroxide and magnesium hydroxide and mixtures thereof.

5. Liquid antacid preparation according to p. 1, where neutralizing the acid compound is calcium carbonate.

6. Liquid antacid preparation according to p. 1, where neutralizing the acid compound is a gel of aluminum hydroxide.

7. Liquid antacid preparation according to p. 1, where neutralizing the acid compound is hydroxylamine sodium carbonate.

8. Liquid antacid drug under item 1, further comprising a preservative.

9. Liquid antacid drug under item 8, wherein the preservative is selected from butylparaben, methyl paraben and propyl paraben.

10. Liquid antacid preparation according to p. 1 containing 1-100 mg/5 ml of hydroxyethyl cellulose.

11. Liquid antacid preparation according to p. 1, further containing a pharmaceutically effective amount of an antagonist of histamine H2 receptor.

12. Liquid antacid preparation according to p. 11, where the antagonist of histamine H2 receptor selected from cimetidine, ranitidine, nizatidine and famotidine.

13. Liquid antacid preparation according to p. 12, containing from 100 mg to about 400 mg of cimetidine per dose.

14. Liquid antacid preparation according to p. 12, containing from 50 to ml.

16. A method of treating gastrointestinal disorders in humans, where it is desirable to neutralize the acid action, which includes the introduction of a specified subject an effective amount of a liquid antacid compositions under item 1.

17. A method of treating gastrointestinal disorders in humans, where it is desirable to neutralize the acid action, which includes the introduction of a specified subject an effective amount of a liquid antacid compositions under item 11.

18. The method according to p. 16, where gastrointestinal disorder selected from the group including indigestion, heartburn, dyspepsia, increased gastric acidity and reflux esophagitis.

19. The way the final sterilization of liquid antacid preparation containing as a suspending agent, hydroxyethyl cellulose, consisting in pasteurization at 60-100°C.

 

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