CN1931367A - Application of alginate in preparing medicine smell masking prepn - Google Patents

Abstract

The invention discloses the application of alginate in the preparation of preparations for masking bad smell of medicines. The application is to encapsulate the drug that needs to be taste-masked with insoluble alginate to make an oral preparation. The preparation prepared by using the application can effectively cover the bad smell of the medicine, and the method for realizing the application provided by the invention is simple and easy, and is suitable for large-scale industrial production.

Description

Application of alginate in the preparation of preparations for masking bad smell of medicines

technical field

The invention belongs to the field of medicine and relates to the application of alginate in the preparation of preparations for masking the bad smell of medicines.

Background technique

Many drugs, such as most inorganic salts, alkaloids, protein polypeptides, macrolide antibiotics, garlic oil, etc., have strong bitterness and peculiar smell, which greatly restricts their formulation development and clinical use. . At present, there are generally three methods for covering the bad smell of drugs: (1) transforming the structure of the drug to prepare a non-bitter prodrug; (2) adding flavoring agents, fragrances, glues, etc. to cover Bitter or paralyzed taste buds, in order to achieve the purpose of taste masking; (3) use preparation methods such as coating, inclusion, microcapsules, etc. to separate the drug from the taste buds on the oral mucosa.

The following is a comparison of the two methods commonly used in pharmacy to mask the bitterness of drugs:

1. Adding flavoring agents: adding sweeteners, flavoring agents, mucilage and other auxiliary materials to numb the taste buds or cover up the bitterness with sweetness or fragrance. This method needs to add a large amount of flavoring agents. Although the method is simple, but It has limited effect on bitter drugs, and has poor taste-masking effect on drugs with large doses.

2. Coating: Coating the drug powder particles is a more effective method to mask the bitter taste. At present, fluidized bed coating and phase separation coagulation are commonly used. Fluidized bed coating is a commonly used method. Generally, the powder needs to be pre-treated. If the powder is too fine, it may agglomerate due to electrostatic interaction and affect the coating effect. The phase separation coagulation method generally requires the addition of organic solvents, which is difficult for industrial production. .

Existing studies believe that there are intramolecular hydrogen bonds in bitter drug molecules, that is, there are hydrogen donor groups and hydrogen acceptor groups in the molecule, and the distance between them (intramolecular hydrogen bond distance) is within 1.5A, which enhances the hydrophobicity of the drug. At the same time, bitter drug molecules often contain other hydrophobic groups, and these groups are easy to combine with the receptors of bitter cells (hydrophobic interaction), which stimulates bitter cells and makes people feel bitter. Therefore, the taste threshold of general bitter substances is much lower than that of sour, sweet, and salty substances, that is, bitter substances are easily adsorbed on the bitter cell receptor membrane, so that the human body can taste bitterness at a very low concentration. In addition, many bitter drugs, such as alkaloids, are mostly positively charged under neutral conditions, and the surface of the bitter receptor membrane is negatively charged, so that positively charged bitter substances are particularly easily adsorbed on the bitter receptor membrane ( electrostatic interaction), so the taste threshold is very low.

Alginate such as sodium alginate is a kind of biological polysaccharide natural polymer compound extracted from algae plants such as kelp and sargassum. It is the main component of seaweed cell wall. After alginic acid is processed, water-soluble alginic acid is obtained sodium salt. Alginate is non-toxic, non-irritating, and has unique physical and chemical properties and good biocompatibility. It is widely used in pharmaceutical preparations, tissue engineering, clinical treatment, cell culture, food processing and other fields. A large number of studies have shown that sodium alginate is not only a safe food additive, but also has lipid-lowering, lead-free and anti-tumor effects. In the United States today, sodium alginate is known as a "wonderful food additive"; in Japan it is known as a "longevity food". At present, the demand for alginate is increasing substantially every year, and its application in various industries is gradually expanding.

Sodium alginate is a white or light yellow powder with high molecular weight, linear shape and high hydratability. It has extremely high viscosity in low-concentration aqueous solution. The molecule has a large number of carboxyl and hydroxyl groups and is negatively charged. Very good thickener, suspending agent, filler, clarifying agent, stabilizer and gelling agent. Sodium alginate can be complexed and cross-linked with metal ions above divalent, and divalent calcium ions are often used in the food and pharmaceutical industry. The resulting calcium alginate is insoluble in water and acid, non-toxic and has sufficient toughness and strength. Calcium alginate gel can be used as a carrier for enzyme immobilization, oral administration of protein and polypeptide drugs, and sustained and controlled release administration. The preparation methods of calcium alginate gel particles mainly include drop method, impregnation method, reverse drop method, composite coagulation method and so on. Among them, the drop method is the easiest to operate, and it is easy to realize the production of mechanized industry.

At present, there is no report on the technology of using alginate to mask the taste of drugs.

Contents of the invention

The purpose of the present invention is to provide the application of alginate in the preparation of taste-masking agent on the basis of comprehensive analysis of domestic and foreign technologies for masking unpleasant odors such as the bitter taste of medicines. The method of this application is suitable for large-scale industrial production.

The purpose of the present invention is achieved through the following technical measures:

Application of alginate in the preparation of preparations for masking bad odor of medicines.

Said application, the method of this application is to wrap the medicine that needs taste-masking with insoluble alginate to prepare oral preparation.

Said application, the method is to add the drug that needs to be taste-masked to the soluble alginate solution, drop into the solution containing divalent or more than divalent metal ions to fully react, and form insoluble alginate particles wrapped with the drug, Filter and dry.

Said application, wherein the method of forming the insoluble alginate particles wrapped with drugs is prepared by drop method, emulsification method, dipping method, reverse drop method, composite coacervation method, centrifugation method, spray method or spray condensation method.

Said application, wherein the soluble alginate is one or more of sodium alginate and potassium alginate.

Said application, wherein the insoluble alginate is calcium alginate.

In the above application, the drugs that need to be taste-masked are macrolide antibiotics, alkaloid drugs, protein polypeptide drugs, and traditional Chinese medicine extracts with pungent odors. Among them, macrolide antibiotics are azithromycin, roxithromycin or clarithromycin; alkaloid drugs are berberine hydrochloride; protein polypeptide drugs are pepsin; garlic oil.

Described application, wherein oral preparation is granule, suspension, tablet, capsule.

Taste-masking preparations such as roxithromycin, azithromycin, berberine hydrochloride, pepsin, garlic oil, etc. have been successfully developed by using the present invention.

According to the requirements of clinical use of drugs, particles of different particle sizes are made (drug loading is 5-95% by weight of the drug in the whole particle, particle size: 5μm-5mm), used to prepare tablets, granules, and suspensions and other oral dosage forms.

Beneficial effects of the present invention:

1. The present invention uses alginate to wrap drugs to form water- and acid-insoluble calcium alginate particles, which are applied to drug loading of bad smell drugs such as bitter taste. On the one hand, a large number of negatively charged groups contained in alginate molecules can act as To shield the positive charge of the bitter drug, so that it has less contact with the taste buds; on the other hand, the alginate is calcified to wrap the drug, and because the calcium alginate is insoluble in water, the amount of the drug dissolved in the oral cavity is greatly reduced, which can reduce the amount of the drug. The contact with the taste buds can effectively play the role of taste masking.

2. The method for realizing the application provided by the present invention is simple and feasible, and is suitable for large-scale industrial production.

Detailed ways

Several embodiments of the present invention will be described below, but the content of the present invention is not limited thereto at all.

Sodium alginate sample source:

Sodium alginate samples 1 (220cps), 2 (430cps), 3 (530cps) - provided by Qingdao Jiaonan Mingyue Seaweed Industry Co., Ltd.;

Sodium alginate samples 4 (model LVCR, viscosity 50cps), 5 (model DMB, viscosity 300cps), 6 (model HVCR, viscosity 400cps), 7 (model Kecosol, viscosity 1300cps) - provided by International Special Products (UK ISP Alginate Ltd) .

Dissolution and taste-masking effect adopt the following methods in the following examples:

Dissolution rate: According to the method specified in the 2005 edition of the Pharmacopoeia, the dissolution rate of the drug contained in it was measured by the basket method, and the dissolution rate was above 70% in 45 minutes.

Taste-masking effect: add the prepared taste-masking granules to an appropriate amount of warm water, take samples at a certain time point to measure the dissolution concentration of the drug in water, whether it is below the bitterness concentration, shake well after 30 minutes and take it orally, there should be no bitterness or unpleasant odor.

Example 1: Preparation of azithromycin-calcium alginate granules, and investigation of bitterness masking effect.

【Preparation of azithromycin-calcium alginate taste-masking granules by drop method】

Suspend azithromycin in 1.5% sodium alginate solution, drop the suspension into 2% calcium chloride solution with a needle at room temperature to form gel particles, calcify it for 1 hour, take it out, filter and rinse Dry, and the resulting dry granules are ready for use.

【Determination of the Bitterness Concentration of Azithromycin】

Prepare azithromycin at a concentration of 10%, add water to dilute it to different concentrations, and repeatedly taste it with multiple people in different orders from thick to thin and thin to thick to determine the concentration without bitterness. After determination, the non-bitter taste concentration of azithromycin is ≤150 μg/ml.

【Investigation on the masking effect of bitter taste】

Place 300mg of the prepared dry granules (containing 250mg of medicine) in 50ml of deionized water, take samples for 5mmin, 10min, and 30min, detect the concentration of the drug in the water and taste the bitter taste of the granules in the oral cavity after 30min, and measure according to the method of Chinese Pharmacopoeia See Table 1 for the dissolution rate of medicine in artificial gastric juice (0.1M hydrochloric acid solution).

Table 1 Dissolution of azithromycin-calcium alginate taste-masking granules in water and artificial gastric juice. sample Dissolution concentration of azithromycin-calcium alginate taste-masking granules in water, μg/ml Dissolution of azithromycin-calcium alginate taste-masking granules in artificial gastric juice for 45 minutes 5min 10min 30min Taste after 30 minutes 1234567 4.145.075.289.326.323.944.76 5.826.948.9211.099.024.597.93 11.0710.8315.3017.6414.749.0610.92 No pain no pain no pain no pain no pain no pain 92% 90% 94% 95% 93% 98% 92%

Observing the above experimental data, the results show that within 30 minutes, the amount of azithromycin released from the taste-masking granules is far lower than the concentration of bitterness, and the amount of azithromycin released in water is not directly related to the type and viscosity of sodium alginate. The drug that can be dissolved in 45 minutes is more than 90%, indicating that its dissolution rate is qualified. It shows that the calcium alginate drug-containing gel particles prepared by the dropping method have good bitterness masking effect, and can dissolve quickly in the stomach.

Example 2: Preparation of Roxithromycin-Calcium Alginate Taste-masking Granules, and Investigation of Bitter Taste Masking Effect

【Preparation of roxithromycin-calcium alginate taste-masking granules by drop method】

Suspend roxithromycin in 1.5% sodium alginate solution (the weight ratio of sodium alginate to drug is 1:6), drop the suspension into 2% calcium chloride solution with a needle at room temperature to form a gel Glue granules were taken out after calcification for 1 hour, filtered, rinsed and dried to obtain dry granules for later use.

【Determination of Roxithromycin Bitterness Concentration】

Prepare roxithromycin at a concentration of 10%, add water to dilute it to different concentrations, and repeatedly taste it with multiple people in different orders from thick to thin and thin to thick to determine the concentration without bitterness. After determination, the non-bitter taste concentration of roxithromycin is ≤60 μg/ml.

【Investigation on the masking effect of bitter taste】

Place 180mg of the prepared dry granules (containing 150mg of medicine) in 50ml of deionized water, take samples for 5mmin, 10min, and 30min, detect the concentration of the drug in the water and taste the bitter taste of the granules in the oral cavity after 30min, and measure according to the method of the Chinese Pharmacopoeia The dissolution rate of medicine in artificial gastric juice (0.1M hydrochloric acid solution), see Table 2

Table 2 Dissolution of roxithromycin-calcium alginate taste-masking granules in water and artificial gastric juice sample Dissolution concentration of roxithromycin-calcium alginate taste-masking granules in water, μg/ml Dissolution of roxithromycin-calcium alginate taste-masking granules in artificial gastric juice for 45 minutes 5min 10min 30min Taste after 30 minutes 1234567 3.2810.046.003.061.643.283.60 3.6013.5412.226.222.186.123.60 12.1212.4817.4813.869.9418.3413.98 No pain no pain no pain no pain no pain no pain 91% 89% 94% 93% 96% 90% 90%

Observing the above experimental data, the results show that within 30 minutes, the release content of roxithromycin from the taste-masking granules is far lower than the bitterness concentration, and the amount of roxithromycin released in water is not directly related to the type and viscosity of sodium alginate. In the artificial gastric juice 45min, the drug can be dissolved more than 90%. It shows that the calcium alginate drug-containing gel particles prepared by the dropping method have good bitterness masking effect, and can dissolve quickly in the stomach.

Example 3: Preparation of Berberine Hydrochloride-Calcium Alginate Taste-masking Granules, and Investigation of Bitter Taste Masking Effect

[Preparation of berberine hydrochloride-calcium alginate taste-masking granules by emulsification method]

Suspend berberine hydrochloride in 2.0% sodium alginate solution (the weight ratio of sodium alginate and drug is 1:1), and add the suspension into liquid paraffin containing an appropriate amount of Tween 80 at normal temperature (suspension The volume ratio to liquid paraffin is 1:4), after magnetic stirring for 30 minutes, 2ml, 2% calcium chloride solution was added dropwise, calcified for 3 hours, the precipitate was taken out after standing for 1 hour, the oil on the surface was washed by filtration, and dried to obtain Dry granules for later use.

【Determination of bitterness concentration of berberine hydrochloride】

Prepare berberine hydrochloride at a concentration of 10%, add water to dilute it to different concentrations, and taste it repeatedly in different orders from thick to thin and thin to thick to determine the concentration without bitterness. It has been determined that the non-bitter taste concentration of berberine hydrochloride is ≤50 μg/ml.

【Investigation on the masking effect of bitter taste】

Put 200mg of the prepared dry granules (containing 100mg of medicine) in 50ml of deionized water, take samples for 5mmin, 10min, and 30min, detect the concentration of the drug in the water and taste the bitter taste of the granules in the oral cavity after 30min, and measure according to the method of Chinese Pharmacopoeia The dissolution rate of medicine in artificial gastric juice (0.1M hydrochloric acid solution), see Table 2

Table 3 Dissolution of berberine hydrochloride-calcium alginate taste-masking granules in water and artificial gastric juice sample Dissolution concentration of berberine hydrochloride-calcium alginate taste-masking granules in water, μg/ml Dissolution of berberine hydrochloride-calcium alginate taste-masking granules in artificial gastric juice for 45 minutes 5min 10min 30min Taste after 30 minutes 1234567 1.131.201.551.301.341.281.60 3.413.542.223.822.182.793.80 10.2311.189.3211.007.748.347.99 No pain no pain no pain no pain no pain no pain 81% 77% 75% 78% 77% 76% 82%

Observing the above experimental data, the results show that within 30 minutes, the release content of berberine hydrochloride from the taste-masking granules is far lower than the bitterness concentration, and the drug can be dissolved in the artificial gastric juice for 45 minutes is greater than 70%. It shows that the calcium alginate-containing drug-masking granules prepared by the emulsification method have a good bitterness masking effect and can dissolve quickly in the stomach.

Example 4: Preparation of Pepsin-Calcium Alginate Taste-masking Granules, and Investigation of Odor Masking Effect

【Preparation of pepsin-calcium alginate taste-masking granules by spraying method】

Suspend pepsin in 1.5% sodium alginate solution (the weight ratio of sodium alginate to drug is 1:6), use a spraying device to spray the suspension into 2% calcium chloride solution at room temperature to form The granules were taken out after 1 hour of calcification, filtered, rinsed and then dried to obtain dry granules for later use.

【Investigation on the masking effect of fishy smell】

Place 250 mg of the prepared granules (containing 200 mg of medicine) in 50 ml of deionized water, take samples for 5 min, 10 min, and 30 min, and taste the fishy taste of the granules in the oral cavity after 30 min, as shown in Table 4.

Table 4 Dissolution of pepsin-calcium alginate taste-masking granules in water sample Taste the off-flavor of the granules over time 5min 15min 30min 123456 No fishy smell No fishy smell No fishy smell No fishy smell No fishy smell No fishy smell No fishy smell No fishy smell Slightly fishy Slightly fishy Slightly fishy Slightly fishy Slightly fishy 7 no fishy smell no fishy smell slightly fishy

Observing the above experimental data, the results showed that the pepsin granule could not taste fishy smell within 15 minutes, but had a little fishy smell within 30 minutes. It shows that the granule has no fishy smell when taken orally within 15 minutes, and has a good taste-masking effect.

Example 5: Preparation of Garlic Oil-Calcium Alginate Taste-masking Granules, and Investigation of Odor Masking Effect

[Preparation of garlic oil-calcium alginate taste-masking granules by centrifugation]

Suspend garlic oil in 2.0% sodium alginate solution (the weight ratio of sodium alginate to garlic oil is 1:2), use centrifugation at room temperature, and throw the suspension into 2% calcium chloride solution to form The granules were taken out after 1 hour of calcification, filtered, rinsed and then dried to obtain dry granules for later use.

【Investigation on the masking effect of fishy smell】

Place 500 mg of the prepared dry granules (containing 300 mg of medicine) in 50 ml of deionized water, take samples for 5 min, 10 min, and 30 min, and taste the odor of the granules in the oral cavity after 30 min, as shown in Table 5.

Table 5 Dissolution of garlic oil-calcium alginate taste-masking particles in water. sample Taste the odor of garlic oil-calcium alginate taste-masking particles after different time 5min 15min 30min 1234567 No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor No Odor

Observing the above experimental data, the results show that the garlic oil-calcium alginate taste-masking particles cannot taste the odor within 30 minutes. It shows that the granule has no odor when taken orally within 30 minutes, and has a good taste-masking effect.

Claims (9)

1, the application of alginate in the preparation medicine smell masking preparation.

2, application according to claim 1, the method that it is characterized in that this application are that the medicine that will need taste masking adopts insoluble alginate parcel, make oral formulations.

3, application according to claim 2, it is characterized in that this method is to add the medicine that needs taste masking in the alginate solution of solubility, splash into and contain bivalence or the above metal ion solution of bivalence is fully reacted, the insoluble alginate granule of medicine has been wrapped up in formation, filter dry getting final product.

4, application according to claim 3 is characterized in that forming the particulate method of the insoluble alginate that has wrapped up medicine and adopts dropping preparation method, emulsion process, infusion process, anti-dripping method, complex coacervation, centrifuging, spurt method or spray condensation method preparation.

5, application according to claim 3, the alginate that it is characterized in that solubility are one or more in sodium alginate, the potassium alginate.

6,, it is characterized in that insoluble alginate is a calcium alginate according to claim 2 or 3 described application.

7,, it is characterized in that the Chinese medicine extract that needs the medicine of taste masking to be macrolide antibiotics, alkaloids medicament, protein and peptide drugs, has the zest abnormal flavour according to claim 2 or 3 described application.

8, application according to claim 7 is characterized in that macrolide antibiotics is azithromycin, Roxithromycin or clarithromycin; Alkaloids medicament is a berberine hydrochloride; Protein and peptide drugs is a pepsin; Chinese medicine extract with strong and stimulating abnormal flavour is an Oleum Bulbus Allii.

9, application according to claim 2 is characterized in that oral formulations is granule, suspensoid, tablet, capsule.