A kind of simethicone powder and its preparation method and application

Abstract

The present invention belongs to the field of pharmaceutical technology, and relates to the treatment of gastric diseases, and in particular to a simethicone powder and its preparation method and application, comprising simethicone, alkaline compounds, fillers, dispersants and flavoring agents. The present invention is prepared into a powder that can be used in combination through creative prescriptions and processes, and is orally used to treat gastric diseases such as gastric acid and abdominal bloating, and can also be used as a defoaming agent before gastrointestinal endoscopy. After administration of different doses, the number of drug-effect hiccups in modeling mice was significantly reduced, and the volume of gastric accumulation was significantly reduced.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical technology, relates to the treatment of gastric diseases, and particularly relates to a simethicone powder and a preparation method and application thereof. Background Art

[0002] Simethicone was developed and marketed by Berlin-Chemie AG in Germany in the 1970s. It is a defoaming agent recognized by the international pharmaceutical field and is included in both the American and British Pharmacopoeias. Its English name is Simethicone or Simeticone. It is used as a defoaming agent or antacid in gastrointestinal drug formulations. Since the Ministry of Health of my country allowed the import of simethicone emulsion (trade name: Apemisin, Bosi) produced by Berlin-Chemie in Germany in 2001, the drug has been widely used in clinical practice.

[0003] So far, many patents of various countries have disclosed preparations of simethicone for acid and flatulence resistance. U.S. Patent No. 4127650 discloses a solid simethicone granule preparation, which encapsulates simethicone in a matrix formed by mixing glycerol and corn syrup particles. Due to the shielding effect of the matrix, the incompatibility with antacids is avoided, and the simethicone can be mixed with antacids to form tablets or capsules.

[0004] US Patent No. 4,906,478 discloses a simethicone preparation, which is a preparation obtained by mixing equal amounts of powdered calcium silicate particles and simethicone, and is further prepared into tablets or capsules for use as an antacid and foam suppressant.

[0005] US Patent No. 5,073,384 discloses a foam suppressor comprising water-soluble gelled maltodextrin and simethicone or silicone or other oils containing silicon dioxide, wherein the maltodextrin accounts for 50-90%, and the maltodextrin can be further prepared into tablets and capsules in the form of particles.

[0006] US Patent USRE35893 discloses a free-flowing mixture consisting of 50-90% water-soluble carbohydrates and 10-50% simethicone or hydrocarbon or silicone oil having a defoaming effect, which can be mixed with pharmaceutically acceptable excipients to form tablets, capsules, granules and other defoaming applications.

[0007] U.S. Patent No. 6103260 discloses an oral solid preparation for defoaming, which is a mixture of simethicone and anhydrous calcium phosphate, and has solid particles with a particle size of less than 1000 microns. Experiments have confirmed that its defoaming ability is more effective than the dosage form disclosed in US4906478.

[0008] US Patent US341742B2 discloses a granular preparation of simethicone mixed with magnesium carbonate, which can avoid the adhesion of simethicone or other excipients to the tablet preparation device and does not interfere with the defoaming effect of simethicone. Patent CN101229187A discloses a gastrointestinal gas exhaust agent - simethicone emulsion. The emulsion contains simethicone emulsion as an active ingredient and a pharmaceutically licensed carrier / excipient as an inactive ingredient, wherein the emulsion content of simethicone accounts for 25%-35% of the total content of the simethicone emulsion, the content of inactive ingredients accounts for 65-75% of the total content of the simethicone emulsion, and the particle size of simethicone is 10-50nm. The simethicone emulsion of the invention has an excellent gas exhaust effect, which is 150 times that of dimethicone. It can be used in any group of people with flatulence symptoms, including infants, pregnant women, and diabetics, and is safe and efficient.

[0009] Patent 101836996A discloses an oral solid preparation with loperamide hydrochloride and simethicone as main ingredients. It is a solid preparation made by loperamide hydrochloride and simethicone with pharmaceutically acceptable excipients through formulation technology. The oral solid preparation of the invention has stable and controllable quality. It is safe and effective.

[0010] Patent 102470183B discloses a pharmaceutical composition containing simethicone / dimethicone. It is mainly composed of 1-1000 parts of acetylcysteine ​​or its pharmaceutically acceptable salt and 1-500 parts of dimethicone or simethicone. It can be made into various pharmaceutically acceptable dosage forms and used as an auxiliary medication before digestive endoscopy and treatment or imaging examination. Compared with the same dose of acetylcysteine ​​or dimethicone or simethicone alone, it has a stronger defoaming effect and mucus removal effect.

[0011] Patent CN102552189A discloses a method for preparing simethicone pills with gelatin glycerol as the matrix. The method is to prepare simethicone into an oil-in-water emulsifier and then prepare the pills. The invention can ensure that the simethicone contained in the simethicone pills can be fully emulsified, thereby exerting its defoaming ability, and the process is simple and easy to control.

[0012] Patent CN102688251B discloses a simethicone solid composition, which is mainly made of simethicone, glucose and pharmaceutically acceptable excipients through formulation technology. The obtained oral solid preparation has stable, controllable, safe and effective quality.

[0013] Patent publication number CN104523717A discloses a simethicone otilonium bromide tablet and a preparation method thereof, which has low cost, simple preparation method and is suitable for industrial production.

[0014] Patent CN105055326B discloses a simethicone dry suspension and a preparation method thereof, which contains 4% by mass of simethicone and a pharmaceutically acceptable carrier, is simple to operate, low in cost, and suitable for industrial production. The obtained product has the advantages of good taste, uniform distribution, good solubility, and stable quality.

[0015] Patent CN105878183A discloses a preparation process of a simethicone self-emulsifying preparation, which contains simethicone 2.0-6.0%, emulsifier 2.0-30.0%, co-emulsifier 1.0-20.0%, wetting agent 0-10.0% and pharmaceutically acceptable solid adsorption material 50.0-90.0%. The preparation operation is simple, the cost is low, and it is suitable for industrial production. The obtained product has the advantages of good taste, uniform distribution, good solubility and stable quality. It is quick to dissolve and easy to take, and has a quick onset of action. It is suitable for the elderly, children and people with dysphagia, and increases patient compliance.

[0016] In actual clinical applications, the solid dosage forms in the prior art are prone to turbidity in the gastrointestinal tract of patients after administration, which affects the detection field of gastroscopy and colonoscopy.

[0017] Li Ran et al. (Drugs & JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES) Vol. 61 No. 10 Oct. 2023) verified that taking the prepared sodium bicarbonate solution before gastroscopy can achieve a bubble removal effect roughly equivalent to that of the commonly used bubble removal drugs in clinical practice, and does not affect the detection rate of microscopic lesions.

[0018] There is no record of a powder in the prior art that combines sodium bicarbonate and a pharmaceutically acceptable alkaline compound with simethicone. Summary of the invention

[0019] In view of the above problems, the present invention provides a simethicone powder and a preparation method and application thereof.

[0020] In order to achieve the above object, the technical solution adopted by the present invention is:

[0021] A simethicone powder specifically comprises the following components:

[0022] Preferably, the flavoring agent is further included, wherein the flavoring agent is essence and sodium citrate, the ratio of the essence to sodium citrate is 1:1, and the essence is any one of strawberry essence, cherry essence and banana essence.

[0023] Preferably, the alkaline compound is sodium bicarbonate, and the particle size of the sodium bicarbonate is ≤3000 nanometers.

[0024] Preferably, the filler is starch, mannitol or carboxymethyl cellulose.

[0025] Preferably, the dispersant is colloidal silicon dioxide.

[0026] A method for preparing simethicone powder specifically comprises the following steps:

[0027] (1) Weigh the prescribed amount of filler and put it into a mixing container, slowly drop the weighed simethicone into the container while stirring, and grind and mix after the dropwise addition is complete;

[0028] (2) adding dispersant silicon dioxide to the solid mixture and mixing thoroughly to obtain a solid mixture 1;

[0029] (3) weighing a prescribed amount of sodium bicarbonate and a pharmaceutically acceptable alkaline compound, and thoroughly grinding and mixing them with a dispersant, silicon dioxide, to obtain a solid mixture 2;

[0030] (4) The solid mixture 1 and the solid mixture 2 are fully mixed by a three-dimensional mixing device, and the flavoring agent is finally added to the total mixture, sieved, and packaged into aluminum foil / polyethylene composite bags for pharmaceutical packaging.

[0031] The simethicone powder prepared by the above preparation method is an oral dispersant, which is used to treat gastric acid and abdominal bloating, and can also be used as a defoaming agent before gastrointestinal endoscopy.

[0032] Compared with the prior art, the advantages and positive effects of the present invention are:

[0033] The pharmaceutically acceptable alkaline compound of the present invention can quickly and effectively reduce the concentration of gastric acid, and simethicone can then play a role in eliminating gas in the gastrointestinal tract. While eliminating the symptoms of flatulence, it is also beneficial for the pharmaceutically acceptable alkaline compound to contact with gastric juice. At the same time, the pharmaceutically acceptable alkaline compound and gastric acid will produce bubbles after the reaction, and simethicone will eliminate them in time. After eliminating gastric acid and bubbles, the inspection field of the gastrointestinal tract will be very clear, and doctors can better observe the patient's gastrointestinal diseases;

[0034] The present invention uses a creative prescription and process to prepare a powder that can be used in combination, and is orally used to treat gastric diseases such as gastric acid and abdominal bloating, and can also be used as a defoaming agent before gastrointestinal endoscopy. After administration of different doses, the number of hiccups in the modeling mice was significantly reduced, and the volume of gastric accumulation was significantly reduced. DETAILED DESCRIPTION

[0035] In order to more clearly understand the above-mentioned purpose, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

[0036] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0037] The present invention provides a simethicone powder and a preparation method and application thereof. Before talking about the powder, let's first understand simethicone. Simethicone is a composite of α-(trimethylsilyl)-ω-methyl poly[oxy(dimethylsilylene)] (also known as dimethicone or polydimethylsiloxane) and silicon dioxide, and its molecular formula is (CH3)3Si[-O-Si(CH3)2] n CH3+SiO2, CAS No. 8050-81-5. Simethicone contains not less than 90.5% and not more than 99% of polydimethylsiloxane and not less than 4% and not more than 7% of silicon dioxide. It is a translucent, gray, viscous liquid that is easily soluble in chloroform, ether or toluene, and insoluble in water and ethanol. The active component of simethicone is polydimethylsiloxane, and silicon dioxide is mainly used to enhance the defoaming performance of silicone. The structure is as follows:

[0038]

[0039] The silicone defoaming agent simethicone has good medicinal safety. It is used as an excipient in food, oral and topical preparations and is considered to be relatively non-toxic and non-irritating. Oral simethicone can reduce the surface tension of bubbles in the gastrointestinal tract, causing the bubbles to merge and burst. It is clinically used to improve indigestion or excessive foaming caused by gastroesophageal reflux disease, resulting in flatulence and stomach discomfort. Therefore, simethicone has been widely used in gastrointestinal drug formulations abroad. After oral administration, it is not absorbed and is excreted as the original drug after intestinal transport. It is safe and effective. Simethicone is an effective treatment for abdominal pain in infants. Taking 20-40 mg with food can improve infant colic. In addition, simethicone can improve the clarity of B-ultrasound, gastroscopy, colonoscopy, and radiological examinations.

[0040] Simethicone is a viscous liquid surfactant that is almost insoluble in water. It forms droplets in an acidic environment (artificial gastric juice), is evenly dispersed in the system, and produces turbidity; sodium bicarbonate and pharmaceutically acceptable alkaline compounds are solids that are soluble in water and significantly neutralize H+ ions in an acidic environment.

[0041] A simethicone powder and a preparation method thereof.

[0042] Table 1, formula of simethicone powder

[0043]

[0044] Table 2, formula of simethicone powder

[0045]

[0046] Table 3, Simethicone powder formula

[0047]

[0048] Table 4, Simethicone powder formula

[0049]

[0050] Prescription 01-1~04-10 The preparation method of simethicone powder for treating gastric acid, gastric flatulence, and gastrointestinal endoscopy detection defoaming comprises the following steps:

[0051] Weigh the prescribed amount of filler and put it into a mixing container, slowly drop the weighed simethicone into the container while stirring, stir and mix after the dropwise addition is complete, grind with a colloid mill to less than 30 microns, and obtain a mixture for use;

[0052] Adding colloidal silicon dioxide to the solid mixture and mixing thoroughly to obtain a solid mixture 1;

[0053] Weigh the prescribed amount of sodium bicarbonate and a pharmaceutically acceptable alkaline compound, fully grind and mix with dispersant silicon dioxide, and grind with a colloid mill to less than 30 microns to obtain a solid mixture 2;

[0054] The solid mixture 1 and the solid mixture 2 are fully mixed by a three-dimensional mixing device, and the flavoring agent is finally added to the total mixture, sieved, and packaged into aluminum foil / polyethylene composite bags for pharmaceutical packaging to obtain simethicone powders 01-1 to 04-10, batch numbers ZJ-230717-01-1 to ZJ-230717-04-10.

[0055] The appearance and related parameters of the obtained simethicone powder are as follows:

[0056] Appearance

[0057] Method: Take a small amount of solid and observe visually in a bright place.

[0058] Results: Simethicone powders 01-1 to 04-10 were all white powders.

[0059] granularity

[0060] Method: According to the Chinese Pharmacopoeia, the particle size of the sample was measured using a laser particle size analyzer.

[0061] Result: less than or equal to 30 microns.

[0062] Example 2: Stability test

[0063] Methods: The prepared simethicone powder and the marketed simethicone emulsion were placed at high temperature of 60℃ for 5 days, 10 days and 30 days; and exposed to light for 5 days and 10 days, and their stability and defoaming ability were detected.

[0064] Defoaming ability determination method: 1) Preparation of 1% Triton X-100 solution: Take about 5g of Triton X-100, weigh accurately, place in a 1000ml beaker, add 500ml of water, place in a 60℃ water bath for 15 minutes, shake gently until uniform, let it cool to room temperature, and set aside; 2) Operation procedure: Take several portions of 50mL of non-foaming 1% Triton X-100 solution, carefully inject them into clean 250mL stoppered measuring cylinders, add this product, and place them in the same measuring cylinder; add 4ml of water to the measuring cylinder without sample as a blank. Seal the measuring cylinder, shake it up and down vigorously 5 times, leave it for 1 minute, and measure the foam height. Take the foam volume of the measuring cylinder without sample as 100%, and calculate the foam height percentage of each sample.

[0065] Results: Under high temperature and light conditions, the simethicone powder prepared by the present invention has excellent defoaming ability and is stable to temperature and light; the marketed simethicone emulsion is sensitive to light and high temperature. After 10 days of light exposure, the emulsion precipitates and shows obvious stratification, which destroys the uniformity of the preparation product and leads to inaccurate product dosage; in addition, under light conditions, the defoaming ability of the simethicone emulsion is seriously reduced and the stability is deteriorated.

[0066] Table 5 Stability test data-1

[0067]

[0068] Table 6 Stability test data-2

[0069]

[0070] Example 3: Stability test in artificial gastric juice

[0071] Method: Preparation of artificial gastric juice solution: measure 10 ml of artificial gastric juice respectively, put it into a 20 ml beaker, keep it at 37.5℃ for 20 minutes, and set aside; add each sample respectively, observe and record the state of the solution; after keeping it for 30 minutes, observe and record the state of the solution; after vigorously shaking for 1 minute, observe and record the state of the solution.

[0072] Results: After each sample was added to artificial gastric juice, the simethicone emulsion showed flocculent precipitation, which was slightly dissolved after being placed at 37.5°C for 30 minutes, and granular substances still adhered to the bottle wall after shaking; the simethicone powder prepared by the present invention was basically dissolved, and the solution was clear. After the sample precipitated, it could not be defoamed better, which affected the inspection field of the gastroenteroscopy.

[0073] Table 7 Stability test in artificial gastric juice

[0074] Prescription 01-5 Simethicone emulsion Before adding sample The solution is slightly turbid The solution is slightly turbid Add sample Gradually dissolve Flocculent precipitation occurs, and granular substances adhere to the bottle wall <![CDATA[Placement 30min > Basically dissolved (solution clear) A small amount of precipitation, turbid solution, and granular substances attached to the bottle wall <![CDATA[Shake 1min > Dissolve (solution clear) Slightly turbid, with granular matter attached to the bottle wall

[0075] Example 4: Animal testing

[0076] Methods: Mice were selected as the experimental system and 40% Triton X-100 solution was given by gavage, 0.5 ml / mouse for membrane formation. After modeling, they were divided into normal control group, model control group, simethicone emulsion group, and simethicone powder 3% (prescription 01-3), 6% (prescription 01-5), 10% (prescription 01-10) three dose groups. After grouping, drug administration was started and the number of hiccups was measured. After 1 hour, the mice were killed by dislocation, the abdominal cavity was opened, the gastrointestinal ends were ligated, and then the gastrointestinal tract was cut to measure the gastrointestinal volume.

[0077] Results: Under the conditions of this experiment, the three doses of simethicone powder prescription 01-3, prescription 01-5, and prescription 01-10 had significant therapeutic effects on the gastrointestinal bloating model induced by Triton in mice, reducing the number of animal hiccups and the volume of the animal's swollen stomach, and there was no change in gastric tissue pathology. The effect of simethicone powder prescription 01-5 on improving hiccups in the gastrointestinal bloating model induced by Triton in mice was much stronger than that of simethicone emulsion, and the three doses were all stronger than simethicone emulsion in improving gastric volume.

[0078] Table 8 Animal efficacy test

[0079] Model comparison Normal control Prescription 01-3 Prescription 01-5 Prescription 01-10 Simethicone emulsion Number of hiccups (times / 1h) 66 0 23 8 12 27 Gastric volume (ml) 4.5±0.2 3.1±0.2 3.3±0.3 3.2±0.3 3.2±0.3 4.2±0.4

[0080] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes and apply it to other fields. However, any simple modification, equivalent change and modification made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A simethicone powder, characterized in that, Specifically include the following components: The alkaline compound is sodium bicarbonate, and the particle size of the alkaline compound is ≤3000 nanometers; The dispersant is colloidal silicon dioxide; The filler is mannitol or carboxymethyl cellulose.

2. A simethicone powder according to claim 1, characterized in that, The invention also includes a flavoring agent, which is an essence and sodium citrate, the ratio of the essence to the sodium citrate is 1:1, and the essence is any one of strawberry essence, cherry essence and banana essence.

3. A method for preparing the simethicone powder according to any one of claims 1-2, characterized in that: The specific steps include: (1) Weigh the prescribed amount of filler and put it into a mixing container, slowly drop the weighed simethicone into the container while stirring, and grind and mix after the dropwise addition is complete; (2) adding a dispersant to the solid mixture and mixing thoroughly to obtain a solid mixture 1; (3) weighing a prescribed amount of the basic compound, grinding and mixing it with the dispersant to obtain a solid mixture 2; (4) The solid mixture 1 and the solid mixture 2 are fully mixed by a three-dimensional mixing device, and the flavoring agent is finally added into the total mixture, sieved, and packaged into aluminum foil / polyethylene composite bags for pharmaceutical packaging.

4. Use of the simethicone powder according to any one of claims 1 to 2 or the simethicone powder prepared by the preparation method of claim 3 in the preparation of an oral dispersant for treating gastric acid and abdominal flatulence or in the preparation of a defoaming agent for gastrointestinal endoscopy.

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