CN114288243A - A kind of oral antacid in situ gel and preparation method and application thereof - Google Patents

Abstract

The invention discloses an oral antacid in-situ gel and a preparation method and application thereof, belonging to the field of pharmaceutical preparations. The oral antacid in-situ gel designed by the invention is mainly composed of polymer gel skeleton material, inorganic antacid and a small amount of emulsifier. The gel pills are in liquid suspension stock solution before oral administration. After entering the gastrointestinal tract, the stock solution is emulsified. At the same time, the inorganic antacid in the stock solution is neutralized by gastric acid, releasing divalent ions to trigger cross-linking of the gel skeleton. phase transition to form a gel. On the one hand, the gel of the present invention can continuously release antacids to exert mild local antacid effects, prevent the digestive effects of gastric acid and pepsin on the stomach wall, and alleviate the gastric ulcer caused by long-term use of non-steroidal anti-inflammatory drugs Adverse reactions, improve the patient's medication compliance.

Description

A kind of oral antacid in situ gel and preparation method and application thereof

technical field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an oral antacid in-situ gel and a preparation method and application thereof.

Background technique

Non-steroidal anti-inflammatory drugs (NSAIDs) are the second largest product in my country's pharmaceutical production after anti-infective drugs, and they are widely used. With the rapid aging of my country's population, the incidence of cardiovascular disease is increasing year by year, and patients with cardiovascular disease are often prescribed NSAIDs at the same time. In addition, NSAIDs are commonly used anti-inflammatory, antipyretic and analgesic drugs in general families. These factors make the frequency of clinical application of NSAIDs increase year by year. NSAIDs usually do not cause serious adverse drug reactions when used for short-term analgesia without contraindications. However, when NSAIDs are used for antithrombotic or arthritis treatment, the long course of treatment and the large dose increase the risk of drug use. The clinical manifestations of adverse reactions are epigastric pain, fullness, nausea, heartburn and other symptoms, leading to peptic ulcer, and even complicated by gastrointestinal perforation and bleeding. The main mechanisms of NSAIDs causing adverse reactions in the gastrointestinal tract are as follows: (1) Weakly acidic drugs are deionized in the state of low pH value of gastric juice, become fat-soluble substances, diffuse into gastric mucosal cells, and convert into ionic forms, leading to gastrointestinal effects. (2) NSAIDs reduce the production of gastric mucosal protective substances dinoprostone (PGE2) and prostacyclin (PGI2) by inhibiting the native cyclooxygenase-1 of gastric parietal cells. PGE2 and PGI2 have the physiological effects of stimulating the secretion of gastric mucus and bicarbonate; reducing the permeability of gastric epithelial cells and reducing the reverse diffusion of gastric acid; expanding gastric blood vessels and increasing gastric mucosal blood flow.

After the occurrence of adverse reactions caused by NSAIDs, the clinical countermeasures are to repair the barrier function of the gastric mucosa or reduce the invasion of gastric acid and pepsin to the gastric wall to alleviate the adverse reactions by combining drugs, such as supplementing exogenous prostaglandins (misoprost). alcohol), use a proton pump inhibitor (omeprazole) to suppress gastric acid secretion, supplement inorganic antacids (aluminum-magnesium plus), or use a gastric mucosal protectant (sucralfate). However, combined medication not only increases the patient's medication cost, but also leads to a decrease in patient medication compliance, and may even cause additional adverse reactions.

SUMMARY OF THE INVENTION

In order to reduce the adverse reactions of long-term use of NSAIDs, the present invention provides an oral antacid in situ gel, which can prevent and alleviate gastric peptic ulcers caused by long-term medication by antacid and inhibit the activity of pepsin, and improve the compliance of patients with medication. .

The technical scheme adopted in the present invention is as follows:

An oral antacid in-situ gel, the raw materials include: non-steroidal anti-inflammatory drug, gel skeleton material, inorganic antacid, emulsifier and water.

The antacid in situ gel is a liquid suspension stock solution before oral administration. After entering the gastrointestinal tract, the stock solution is emulsified. At the same time, the inorganic antacid in the stock solution is neutralized by gastric acid and releases divalent cations. The complexation of anionic groups such as carboxyl groups triggers the cross-linking of the gel skeleton, and a phase transition occurs to form a semi-solid gel pellet. The gel structure formed first on the surface of the suspension can act as a barrier to prevent the internal antacid from reacting too quickly with gastric acid, and can achieve a mild antacid effect. The activity of pepsin is also inhibited by the increase of pH, thereby weakening Digestive effects of gastric acid and pepsin on the stomach wall.

Further, the non-steroidal anti-inflammatory drug is selected from indobufen, aspirin, indomethacin, diclofenac or their pharmaceutically acceptable salts, preferably indobufen sodium; One of sodium alginate, gellan gum, pectin or any combination thereof, preferably a combination of sodium alginate and gellan gum; the inorganic antacid is zinc oxide, magnesium oxide, calcium carbonate One or any combination thereof, preferably a combination of zinc oxide and magnesium oxide; the emulsifier is selected from one of Tween 80, Tween 20, and emulsifier OP or any combination thereof, preferably Tween 80.

Further, the raw materials of the oral antacid in situ gel include: indobufen sodium is 10 mg/mL; Tween 80 is 1-5 mg/mL, preferably 2-4 mg/mL; sodium alginate is 1-5 mg/mL 10mg/mL, preferably 3-7mg/mL; gellan gum is 1-10mg/mL, preferably 5-7mg/mL; zinc oxide is 1-10mg/mL, preferably 4-8mg/mL; magnesium oxide is 20-30 mg/mL, preferably 22-26 mg/mL; water 100 mL.

In one embodiment of the present invention, the oral antacid in situ gel, the raw materials include: indobufen sodium 10mg/mL; Tween 80 3mg/mL; sodium alginate 3mg/mL; gellan gum 5mg/mL mL; zinc oxide 4mg/mL; magnesium oxide 26mg/mL; water 100mL.

The above-mentioned oral antacid in situ gel, its preparation method comprises the following steps:

(1) Dissolving or suspending the emulsifier and the non-steroidal anti-inflammatory drug of the recipe quantity in water successively obtains solution A;

(2) the gel skeleton material of recipe quantity is fully swollen in liquid A, and then is dissolved in liquid A through stirring to obtain homogeneous liquid B;

(3) After adding the inorganic antacid in the recipe amount to the liquid B, stirring and dispersing evenly, the suspension stock solution of the antacid in-situ gel is obtained.

The oral antacid in situ gel of the present invention has good long-term suspension stability, mild antacid in vitro up to 2 hours, and in vivo level can effectively antacid for at least 3 hours, which can effectively prevent and alleviate stomach upset caused by long-term use of NSAIDs reaction.

Aiming at the problem that the existing NSAIDs preparations are easily taken for a long time to cause gastric adverse reactions and the like, the invention prepares oral in-situ gel pills with good antacid effect, the preparations can prevent and alleviate peptic ulcers caused by NSAIDs, and improve patients' compliance It is easy to prepare and convenient for industrial production.

Description of drawings

Figure 1 is the in vitro dynamic antacid curve of the oral antacid in situ gel obtained in Example 1.

FIG. 2 shows the results of the in vivo acid suppression test of the oral antacid in situ gel obtained in Example 1. FIG.

3 is the result of the in vivo acute gastric ulcer injury protection test result of the oral antacid in situ gel obtained in Example 1.

FIG. 4 is the result of the in vivo chronic gastric ulcer injury protection test result of the oral antacid in situ gel obtained in Example 1. FIG.

Detailed ways

In situ gel refers to a preparation that is liquid before application, and is in a semi-solid gel state after phase transition under the influence of physiological conditions of the body or other factors after reaching the drug site. According to its formation principle, it can be divided into temperature-sensitive type, ion-sensitive type and pH-sensitive type. Natural anionic polysaccharides such as sodium alginate contain anionic groups such as carboxyl groups in the molecular structure, which undergo complexation under the trigger of divalent cations to form a hydrogel with a three-dimensional network structure, wrapping the contents, and can achieve functions such as slow release.

The present invention designs the in-situ gel with reducing the adverse reactions of long-term administration of NSAIDs as a starting point, mainly by antacid and inhibiting the activity of pepsin to prevent and alleviate gastric peptic ulcer caused by long-term administration, and improve the medication compliance of patients.

The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, but should not be construed as a limitation of the present invention. Modifications or substitutions made to the methods, steps or conditions of the present invention without departing from the spirit and essence of the present invention all belong to the scope of the present invention. In the examples, the experimental methods without specifying the specific conditions and the reagents without specifying the formula are all in accordance with the conventional conditions in the art.

Examples 1 to 4

Oral antacid in situ gel embodiment prescription (100mL) is as follows:

Example 1 Example 2 Example 3 Example 4 indobufen sodium 1g 1g 1g 1g Tween 80 0.3g 0.3g 0.1g 0.5g gellan gum 0.5g 0.5g 0.1g 1g Sodium alginate 0.3g 0.5g 0.1g 1g Zinc oxide 0.4g 0.6g 1g 0g Magnesium oxide 2.6g 2.4g 2g 3g pure water 100mL 100mL 100mL 100mL

Weigh Tween 80 and indobufen sodium in the prescribed amount and dissolve them in 100 mL of pure water in turn to obtain a homogeneous transparent liquid A; add the prescribed amount of gellan gum, stir and disperse evenly, and take a water bath at 80°C for 10 min to prepare a homogeneous transparent liquid B ; Sprinkle the sodium alginate of recipe quantity evenly on the surface of liquid B, fully swell for 12h, then magnetically stir with 500rpm rotating speed for 2h to obtain homogeneous liquid C; Add the zinc oxide of recipe quantity, the magnesium oxide of recipe quantity to liquid C, 500rpm Magnetic stirring for 2h, followed by high-speed disperser stirring at 8000rpm for 5min.

Test Example 1

The oral antacid in situ gel obtained in Example 1 was subjected to an in vitro dynamic antacid test, and the zinc oxide and magnesium oxide compositions of the same quality were used as comparative examples. The in vitro dynamic antacid evaluation was carried out with reference to the Rossett-Rice method. Measure 20 mL of the in-situ gel suspension stock solution obtained in Example 1, drop it into a 100 mL beaker containing 50 mL of 0.1 M HCl through a dropper to form a gel, and then carry out a dynamic acid resistance test, test conditions: 37±1°C A water bath, 100 rpm magnetic stirring, and a constant-flow pump were added dropwise to the test beaker with 0.1 M HCl at a speed of 1 mL/min. The pH meter measures the pH of the liquid in the beaker in real time within two hours, records the pH value of the liquid, and draws the pH change curve with time.

As shown in Figure 1, compared with the comparative examples of zinc oxide and magnesium oxide of the same quality, the oral antacid in situ gel of the present invention maintains the pH between 3-5 for 116.63±0.05min under the in vitro test. The highest pH was 4.62±0.23, and the pH of the liquid in the beaker could almost always be maintained within the ideal antacid range within two hours, and the highest pH did not exceed 5, indicating that it could achieve a mild in vitro antacid effect. While being effective against acid, it can avoid the phenomenon of gastric acid rebound caused by the rapid increase of gastric juice pH.

Test Example 2

The oral antacid in situ gel obtained in Example 1 was subjected to an in vivo acid production test, and commercially available aluminum-magnesium plus suspension (Yangzhou Yiyang Pharmaceutical Co., Ltd.) and physiological saline were used as comparative examples. 18 mice were divided into three groups randomly, half male and half female, fasted for 24 hours. The in situ gel group was administrated with the in situ gel suspension stock solution obtained by specific embodiment 1 by 80mg/kg dose (i.e., 8mL/kg volume), and the other two groups were administrated with commercially available aluminum-magnesium plus suspension by 8mL/kg volume. The mice were sacrificed by de-neck at 0, 0.5, 1, 2, 4, and 6 h. The stomach was taken and dissected. The surface pH of the gastric wall of the glandular stomach was measured with a pH 1.4-3.0 precision test paper, and compared with the standard color card. Photo record.

As shown in FIG. 2 , the oral antacid in situ gel of the present invention can maintain the pH of the gastric wall of the glandular stomach at around 3.0 during the first to 4 hours in mice, and achieve a good in vivo antacid effect.

Test Example 3

The oral anti-acid in situ gel obtained in Example 1 of the present invention was subjected to an in vivo acute gastric ulcer injury protection test, and commercially available aluminum-magnesium plus suspension (Yangzhou Yiyang Pharmaceutical Co., Ltd.) and physiological saline were used as comparative examples. Twelve mice were divided into four groups randomly, with half male and half females, fasting for 24 hours. Except for 3 mice in the blank control group, each mouse was intraperitoneally injected with indobufen sodium solution at a dose of 200 mg/kg. Subsequently, the in situ gel group was given the original solution of the in situ gel suspension obtained in Example 1 at a volume of 8 mL/kg, and the aluminum and magnesium addition group and the normal saline group were given the commercially available aluminum and magnesium addition suspension and 8 mL/kg. Normal saline, the mice were sacrificed by de-neck at the 3rd hour, the stomach was dissected, photographed and recorded, according to the Guth's ulcer index scoring standard (0 points for normal gastric mucosa; 1 point for punctate lesions; 2 points for lesions <1 mm) ; 1 mm < lesion < 2 mm, score 3 points; 2 mm < lesion, score 4 points) to record the damage of gastric ulcer in each mouse. The results of the in vivo acute gastric ulcer injury protection test are shown in Table 1.

Table 1 Results of ulcer index scoring in each group of acute gastric ulcer injury (n=3)

According to Table 1 and Figure 3, the ulcer index scoring results showed that each mouse in the in situ gel group had no bleeding and ulcers, and the anatomical results were similar to those of the blank control group. The mice in the positive control aluminum-magnesium plus group and the negative control normal saline group were injured in different degrees, and the injury occurred in the glandular stomach. The above results show that the oral antacid in situ gel of the present invention can effectively avoid the acute gastric ulcer injury caused by large doses of indobufen sodium to mice, and its protective effect on gastric mucosa is better than that of the positive control aluminum magnesium plus suspension. liquid, the protective effect is obvious.

Test Example 4

The oral antacid in situ gel obtained in Example 1 of the present invention was subjected to an in vivo chronic gastric ulcer injury protection test, and commercially available indobufen tablets (Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd.) and normal saline were used as comparative examples. Thirty mice were divided into three groups randomly, with free access to food and water. Each mouse in each group was administered the antacid in situ gel suspension obtained in Example 1 by gavage at a dose of 160 mg/kg every day, the suspension prepared by grinding commercially available indobufen tablets into powder with the same specifications, and the same volume saline for 14 days. On the 14th day, the mice were sacrificed by cervical dislocation, and the stomach was dissected and photographed for recording. According to the Guth's ulcer index scoring standard (0 points for normal gastric mucosa; 1 point for punctate lesions; 2 points for lesions <1 mm; 2 points for lesions <1 mm; Lesions < 2 mm were scored as 3 points; 2 mm < lesions were scored as 4 points) to record the damage of gastric ulcer in each mouse, and to observe the glandular stomach tissue sections and HE staining. The results of the in vivo chronic gastric ulcer injury protection test are shown in Table 2.

Table 2 Results of ulcer index scoring in each group of chronic gastric ulcer injury (n=10)

As can be seen from Table 2, the incidence of gastric ulcer in the in situ gel group for 14 days was 10% lower than the 40% incidence of injury in the commercially available tablet group, and 3 mice in the commercially available tablet group developed gastric wall thinning. .

It can be seen from Figure 4 that the results of HE staining of the glandular stomach sections of the mice in the in situ gel group showed that the gastric mucosal gland ducts were neatly arranged, which was similar to the section results of the normal saline group, with no obvious abnormality. The results of HE staining of gastric sections showed that the gastric gland ducts were disordered and loose, and the gastric mucosal lamina propria was obviously thinned. The oral antacid in-situ gel of the invention can effectively reduce the incidence and degree of chronic gastric ulcer injury caused by long-term gavage of indobufen in mice, and has obvious protective effect.

Claims (6)

1. An oral antacid in situ gel, characterized in that: the raw materials comprise: non-steroidal anti-inflammatory drugs, gel skeleton materials, inorganic antacids, emulsifiers and water;

the non-steroidal anti-inflammatory drug is selected from indobufen, aspirin, indomethacin, diclofenac or pharmaceutically acceptable salts thereof; the gel framework material is selected from one or any combination of sodium alginate, gellan gum and pectin; the inorganic antacid is one or any combination of zinc oxide, magnesium oxide and calcium carbonate; the emulsifier is selected from one or any combination of tween 80, tween 20 and an emulsifier OP.

2. An oral antacid in situ gel according to claim 1, characterized in that: the non-steroidal anti-inflammatory drug is indobufen sodium, the gel framework material is a composition of sodium alginate and gellan gum, the inorganic antacid is a composition of zinc oxide and magnesium oxide, and the emulsifier is tween 80.

3. An oral antacid in situ gel according to claim 2, characterized in that: the raw materials comprise: 10mg/mL of indobufen sodium, 801-5 mg/mL of tween, 1-10 mg/mL of sodium alginate, 1-10 mg/mL of gellan gum, 1-10 mg/mL of zinc oxide, 20-30 mg/mL of magnesium oxide and 100mL of water.

4. An oral antacid in situ gel according to claim 3, characterized in that: the raw materials comprise: 10mg/mL of indobufen sodium, 802-4 mg/mL of tween, 3-7 mg/mL of sodium alginate, 5-7 mg/mL of gellan gum, 4-8 mg/mL of zinc oxide, 20-30 mg/mL of magnesium oxide and 100mL of water.

5. A process for the preparation of an oral antacid in situ gel according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:

(1) sequentially dissolving or suspending the emulsifier and the non-steroidal anti-inflammatory drug in the formula amount in water to obtain a solution A;

(2) fully swelling the gel framework material in the prescription amount in the liquid A, and then stirring and dissolving the gel framework material in the liquid A to obtain uniform liquid B;

(3) adding the inorganic antacid with the prescription amount into the liquid B, and uniformly stirring and dispersing to obtain the suspension stock solution of the antacid in-situ gel.

6. A non-steroidal anti-inflammatory drug characterized by: an oral antacid in situ gel comprising any one of claims 1-4.

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