CN117883379A

CN117883379A - Oral alkaline solvent composition and preparation method and application thereof

Info

Publication number: CN117883379A
Application number: CN202410059021.4A
Authority: CN
Inventors: 黄旻; 郭晓迪; 冯利萍
Original assignee: Zhejiang Beiling Biomedical Co ltd
Current assignee: Zhejiang Beiling Biomedical Co ltd
Priority date: 2021-02-12
Filing date: 2021-02-12
Publication date: 2024-04-16
Also published as: CN114931552A

Abstract

The invention provides a special alkaline suspension dissolvent and fruity dissolvent which are used for temporarily preparing proper mouthfeel, which is suitable for accurately adjusting dosage of various unstable medicines under acidic condition, not only improves taste and improves patient compliance, but also has adjustable dosage, is especially suitable for the administration of oral preparations for infants, children and dysphagia patients, and is an excellent dissolvent which can be selected by pharmacists when preparing temporary oral liquid medicines.

Description

Oral alkaline solvent composition and preparation method and application thereof

The application is a divisional application of Chinese patent application with the application date of 2021, 2-month and 12-date, the application number of 202110187127.9 and the invention name of 'an oral alkaline solvent composition, and a preparation method and application thereof'.

Technical Field

The invention relates to the field of medicines and foods, in particular to an oral alkaline solvent for oral medicines or foods, and a preparation method and application thereof.

Background

Currently, the design of pharmaceutical dosage forms and specifications approved for sale in the market mainly considers the medication requirements of adults, and the specifications of many medicaments are not marked for use by certain special groups such as infants and children. When the drug is available to infants and children without approval by an authority, it is often not possible to obtain a suitable dosage form for pediatric patients. If a drug has potential therapeutic or life-saving effects but no suitable dosage form is available for selection by children, an alternative approach is to reformulate the dosage form of the commercially available drug into a suitable temporarily formulated drug for use by pediatric patients.

Investigation data shows that temporary dosing is common for pediatric patients of different ages and different disease types. Moreover, many patients use more than one temporary medication for the entire hospital stay, up to 8 medications. The most temporarily formulated drugs are nervous system drugs, cardiovascular system drugs and anti-infective drugs. The frequency and variety of temporary drug formulations used by oncology and cardiothoracic surgery patients is significantly higher than those of other departments (Cai Zhibo et al, chinese journal of pharmacy 2009, 7 months, volume 44, 14).

Methods for temporarily dispensing the drug by pharmacist (or nurse) include drug splitting, milling, split charging, dilution, and the like. However, the accuracy of the dose of the small package obtained by cutting and pulverizing (or removing the capsule shell) and then sub-packaging is hardly ensured. In addition, the dosage difference between the individuals of pediatric patients can reach 50 times, the dosage of the preparation method can not be changed randomly along with the individual change of children, and the needs of different individuals can be met by preparing packages with different specifications. The dosage of the same drug varies widely from neonate to puberty, and physicians often convert the dosage of the drug administered to children according to age, weight or body surface area, often 1/2, 1/4, etc. of the dosage of adults, especially neonates, even 1/10 or less of the dosage of adults. The infant patient can only adopt an adult medicine split-dose mode to treat, and especially, the accurate split-dose of some medicines with narrow treatment window (the difference between the treatment concentration and the concentration generating toxicity is smaller) becomes one of the keys for guaranteeing the infant safety medication.

The tablet has the advantages of convenient administration, convenient storage and the like, is the most commonly used clinical pharmaceutical dosage form, and the dosage of 1/2/, 1/5 tablet and the like is needed for infants, thereby bringing great inconvenience to the administration. For scored tablets, direct hand breaking may be used, such as a cross score on methylprednisolone (trade name: mei Zhuo Le) to help divide the tablet into 1/4 pieces. However, the disadvantage is that for tablets which require 1/3 or 1/5 of the dose, the exact dose cannot be directly obtained by means of scoring.

For non-scored tablets, the tablets may be divided by means of a tool. When the cutting effect of the tablet cutter, the scissors and the kitchen knife is studied, the actual mass and the theoretical mass of the divided dose of the tablet cutter are the closest. However, this method has the disadvantage that the dosage is not directly accurate for tablets which require 1/3 or 1/5 of the dosage.

For administration at 1/5 or 1/6 tablet, the tablet may be divided into sub-divided parts after grinding. If the dosage of the phenobarbital tablet (30 mg for each tablet) is required to be adjusted to 1/6 tablet, 1 tablet can be taken and put into a mortar to be ground into fine powder, or the tablet is put into a small bowl to be ground into fine powder by a spoon and then visually estimated into 6 bags, but the accurate dosage cannot be ensured and the error is larger.

Part of the capsule can also be opened, and the medicine powder is poured out and then packaged by the method. The disadvantage of this method is that the smaller the dose, the less prone to sub-packaging and the larger the error; the packaged medicine is easy to absorb moisture and has uncertain stability. Therefore, the influence of environmental factors (such as humidity, illumination, microorganisms, storage conditions and the like) should be avoided as much as possible, and the packaging of the split-dose medicine should be used as early as possible.

The whole tablet is ground into powder or the capsule content is poured into a medicine taking cup, a certain amount of water is added according to the dosage and specification to prepare a liquid preparation, and then the required dosage is extracted. Probiotic preparations commonly used for infants are divided into doses by this method. Such as Bifidobacterium Lactobacillus triple viable bacteria tablet (trade name: jin Shuangqi) can be taken by pulverizing the tablet and dissolving in warm milk. The method has the advantages of easy quantitative measurement after preparing liquid, and convenient addition of fruit juice and other corrective to improve taste. However, it is important to note whether the drug has an interaction with the flavoring agent such as milk and juice, and the drug with poor stability is not suitable for this method.

The oral solvent is a solvent which is convenient for the administration of oral preparations, can help the medicine to be uniformly dispersed, and has the characteristics of convenient administration, accurate dosage and quick absorption in vivo. At present, the countries such as the united states, europe, united kingdom, japan and the like, internationally use oral vehicles for tablet split dosage, and the countries have no commercialization. The split-dose tablets are taken by adding water after breaking off, the dosage of the tablets is small, the dosage of the tablets is more than one quarter of the dosage required for children to take medicine, the tablet powder is lost in the breaking-off process, pollution is caused, the dosage is incorrect, and the broken-off tablets have special bitter taste, so that patients cannot accept the tablets easily, the taking of the tablets is difficult, the curative effect is influenced, and adverse reactions are caused.

For some APIs that are unstable under acidic conditions, such as omeprazole, lansoprazole, rabeprazole, duloxetine, aspirin, posaconazole, ilaprazole, esomeprazole magnesium, dexlansoprazole, pantoprazole, lansoprazole, mesalamine, diclofenac sodium, paroxetine, meclofenozole sodium, cimecoxib, ibuprofen, erythromycin, etc., since such drugs are easily degraded in acidic solutions, an alkaline suspension vehicle is provided for this purpose that stabilizes them. However, the basic oral solvent has not been reported yet.

Disclosure of Invention

In view of the above problems, the present invention aims to provide an alkaline solvent which is specially used for temporarily preparing a proper taste, is suitable for accurately adjusting the dosage of various drugs which are unstable under an acidic condition, not only improves the taste and improves the compliance of patients, but also has adjustable dosage, and is particularly suitable for the administration of oral preparations for infants, young children and dysphagia patients. The product can also be used for dysphagia patients, and can be used for supplementing daily needs by dissolving vitamins or other dietary supplements with vehicle. For the behavior that patients with neurological diseases refused to take medicines, the medicines can be dissolved by the solvent for flavoring, so that the compliance is improved.

The invention provides an oral alkaline suspension solvent composition, which comprises the following components: microcrystalline cellulose 0.2-2.8% (m/V), sodium carboxymethylcellulose 0.02-1.5% (m/V), xanthan gum 0.05-3.8% (m/V), carrageenan 0.05-0.6% (m/V), preservative 0.033-0.288% (m/V), buffer 0.11-11.05% (m/V), defoamer 0.01-1% (V/V) and water 99.0-99.99% (V/V), and the pH range is 7.5-11.

In a preferred embodiment of the present invention, the buffer in the oral alkaline suspension vehicle is any buffer capable of maintaining the vehicle at a pH of 7.5 to 11 in the aqueous state, optionally from phosphoric acid/sodium hydroxide buffer, dipotassium hydrogen phosphate-sodium hydroxide buffer, phosphate buffer, sodium acetate buffer, or any combination thereof, preferably 1% -10% (m/V) of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, or any combination thereof. In another preferred embodiment of the present invention, the buffering agent in the oral alkaline suspension vehicle comprises 0.01% -1.5% (m/V) sodium acetate, 0.07% -9.2% (m/V) dipotassium hydrogen phosphate, and 0.03% -0.35% (m/V) trisodium phosphate.

In a preferred embodiment of the present invention, the antifoaming agent in the oral basic suspension is selected from the group consisting of silicone emulsions, higher fatty acid ester complexes, polyoxyethylene polyoxypropylene pentaerythritol ethers, polyoxyethylene polyoxypropylene alcohol amine ethers, polyoxypropylene glycerol ethers, polyoxypropylene polyoxyethylene glycerol ethers, polydimethylsiloxanes, or combinations thereof, preferably polydimethylsiloxanes. The defoamer content is 0.01% to 1% (V/V), preferably 0.01% to 0.5% (V/V), more preferably 0.04% to 0.29% (V/V). In another preferred embodiment of the present invention, the antifoaming agent in the oral alkaline suspension is polydimethylsiloxane in an amount of 0.04% -0.29% (V/V).

In a preferred embodiment of the present invention, the preservative in the oral alkaline suspension vehicle is selected from methyl benzoate, propyl benzoate, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, calcium propionate, chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or a combination thereof, preferably potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or a combination thereof. In another preferred embodiment of the present invention, the preservative in the oral alkaline suspension vehicle comprises methylparaben 0.003% -0.008% (m/V) and potassium sorbate 0.03% -0.28% (m/V).

In a preferred embodiment of the present invention, the water in the oral alkaline suspension is selected from mineral water, purified water, space water or water for injection, preferably purified water.

In a preferred embodiment of the present invention, the oral alkaline suspension vehicle further comprises 0.04% -35% (m/V) of a flavoring agent, more preferably the flavoring agent is present in an amount of 2% -25% (m/V), and even more preferably the flavoring agent is present in an amount of 3% -20% (m/V). The flavoring agent is selected from sucrose, fructose, maltose, lactose, starch sugar, saccharin sodium or a combination thereof. In a preferred embodiment of the present invention, the oral alkaline suspension vehicle contains 1% -35% (m/V) sucrose. In a preferred embodiment of the invention, the oral alkaline suspension vehicle contains 0.04% to 0.3% (m/V) sodium saccharin. In another preferred embodiment of the present invention, the oral alkaline suspension vehicle contains 3% to 20% (m/V) sucrose and 0.05% to 0.28% (m/V) sodium saccharin. In a preferred embodiment of the invention, the oral alkaline suspension vehicle is a sugarless formulation when it is free of flavoring agents, suitable for use in diabetics or in patients who do not like sweet taste. When the oral alkaline suspension solvent contains a flavoring agent, the oral alkaline suspension solvent has better mouthfeel due to more sugar, and is suitable for infants.

In a preferred embodiment of the present invention, the pH of the oral alkaline suspension vehicle is preferably in the range of pH7.5 to 10.5, more preferably in the range of pH8.0 to 9.5.

As an exemplary preferred embodiment, the present invention provides an oral alkaline suspension vehicle comprising the following ingredients: microcrystalline cellulose 0.25% -1.8% (m/V), sodium carboxymethylcellulose 0.03% -1.2% (m/V), xanthan gum 0.06% -3% (m/V), carrageenan 0.06% -0.5% (m/V), sodium acetate 0.03% -1.45% (m/V), dipotassium hydrogen phosphate 0.08% -3.2% (m/V), trisodium phosphate 0.05% -0.3% (m/V), methylparaben 0.04% -0.28% (m/V), potassium sorbate 0.035% -0.28% (m/V), polydimethylsiloxane 0.05% -0.25% (V/V) and purified water 99.75% -99.95% (V/V), and the pH range is 8.0-9.5.

As an exemplary further preferred embodiment, the present invention provides an oral alkaline suspension vehicle comprising the following ingredients: microcrystalline cellulose 0.25% -1.8% (m/V), sodium carboxymethylcellulose 0.03% -1.2% (m/V), sucrose 1% -35% (m/V), xanthan gum 0.06% -3% (m/V), carrageenan 0.06% -0.5% (m/V), sodium acetate 0.03% -1.45% (m/V), dipotassium hydrogen phosphate 0.08% -3.2% (m/V), trisodium phosphate 0.05% -0.3% (m/V), methylparaben 0.04% -0.28% (m/V), potassium sorbate 0.035% -0.28% (m/V), polydimethylsiloxane 0.05% -0.25% (V/V) and purified water 99.75% -99.95% (V/V), and the pH range is 8.0-9.5.

The oral alkaline suspension solvent prepared by the invention is very suitable for preparing the drug which is easy to degrade in an acidic solvent into an oral suspension, wherein the drug which is unstable under the acidic condition is selected from omeprazole, lansoprazole, rabeprazole, duloxetine, aspirin, posaconazole, ilaprazole, esomeprazole magnesium, dexlansoprazole, pantoprazole, mesalamine, diclofenac sodium, paroxetine, sodium mycophenolate, cimicotin, ibuprofen, erythromycin and the like or a combination thereof. Because of containing the defoamer and a proper amount of preservative, the anti-foam agent has mild property and has a certain buffering effect on the medicament when being matched with the medicament, the medicament is more stable in an alkaline suspension solvent and is not easy to degrade.

The pH range of the oral alkaline suspension dissolvent prepared by the invention is 7.5-11 (preferably, the pH range is 8.0-9.5), which provides dissolvent with good stability for preparing temporary oral liquid medicine. In order to improve the compliance of patients, and in particular to be better suitable for the drug administration of children, the oral alkaline suspension solvent can be further buffered and seasoned to improve the taste of the prepared temporary oral drug solution and provide a more complete fruity solvent.

Accordingly, another aspect of the present invention is to provide an oral fruity vehicle composition comprising the following components: 3-15% (V/V) of glycerin, 2-16% (V/V) of sorbitol solution, 0.04-0.5% (m/V) of xanthan gum, 0.11-11.05% (m/V) of buffering agent, 0.006-0.6% (m/V) of preservative, 0.005-0.1% (m/V) of chelating agent, 0.01-0.5% (V/V) of fruity flavoring agent and 68.5-94.99% (V/V) of water, and the pH range is 7.5-11.

In a preferred embodiment of the present invention, the buffer in the oral fruity vehicle is any buffer capable of maintaining the vehicle at a pH of 7.5 to 11 in aqueous solution, optionally from phosphoric acid/sodium hydroxide buffer, dipotassium hydrogen phosphate-sodium hydroxide buffer, phosphate buffer, sodium acetate buffer or any combination thereof; preferably 1% to 10% (m/V) potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, or any combination thereof. In another preferred embodiment of the present invention, the buffering agent in the oral fruity vehicle comprises 0.01% -1.5% (m/V) sodium acetate, 0.07% -9.2% (m/V) dipotassium hydrogen phosphate, and 0.03% -0.35% (m/V) trisodium phosphate.

In a preferred embodiment of the present invention, the preservative in the oral fruity vehicle is selected from methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, calcium propionate, chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or a combination thereof, preferably potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or a combination thereof. In another preferred embodiment of the present invention, the preservative in the oral fruity vehicle comprises 0.001% -0.2% (m/V) methylparaben, 0.001% -0.1% (m/V) propylparaben and 0.004% -0.3% (m/V) potassium sorbate.

In a preferred embodiment of the present invention, the fruit flavor in the oral fruit flavor vehicle is selected from natural flavors, such as orange, cherry, apple, banana, strawberry, grape, lemon, melon or yogurt flavored natural flavors, preferably cherry or orange flavored natural flavors. In another preferred embodiment of the present invention, the fruit flavor in the oral fruit flavor vehicle is cherry flavor 0.05% -0.2% (V/V).

In a preferred embodiment of the present invention, the chelating agent in the oral fruity vehicle is selected from ethylenediamine tetraacetic acid (EDTA), aminotriacetic acid (NTA), diethylenetriamine pentaacetic acid (diethylene triamine CA), citric Acid (CA), tartaric Acid (TA), gluconic Acid (GA), hydroxyethylethylenediamine triacetic acid (HEDTA), dihydroxyethylglycine (DEG) and the like. In another preferred embodiment of the present invention, the chelating agent is disodium edetate 0.005% -0.1% (m/V).

In a preferred embodiment of the present invention, the water in the oral fruity vehicle is selected from mineral water, purified water, space water or water for injection, preferably purified water.

In a preferred embodiment of the present invention, the oral fruity vehicle further comprises 0.04% to 35% (m/V) of a flavoring agent, more preferably the flavoring agent is present in an amount of 2% to 25% (m/V), and more preferably the flavoring agent is present in an amount of 3% to 20% (m/V). The flavoring agent is selected from sucrose, fructose, maltose, lactose, starch sugar, saccharin sodium or a combination thereof. In a preferred embodiment of the present invention, the oral fruity vehicle contains 1% to 35% (m/V) sucrose. In a preferred embodiment of the invention, the oral fruity vehicle contains 0.04% to 0.3% (m/V) sodium saccharin. In another preferred embodiment of the present invention, the oral fruity vehicle contains 3% to 20% (m/V) sucrose and 0.05% to 0.28% (m/V) sodium saccharin. In a preferred embodiment of the invention, the oral fruity vehicle, when free of flavoring, is a sugarless formulation suitable for diabetics or patients who do not like sweet taste. When the oral fruity solvent contains a flavoring agent, the oral fruity solvent has better mouthfeel due to more sugar, and is suitable for infants.

In a preferred embodiment of the present invention, the oral fruity vehicle further comprises a pigment in a ratio of 0.05% to 0.2% (V/V), more preferably in a ratio of 0.1% to 0.15% (V/V). In a preferred embodiment of the present invention, the oral fruity vehicle contains 0.1% to 0.15% (V/V) pink pigment.

In a preferred embodiment of the present invention, the oral fruity vehicle pH ranges more preferably from pH7.5 to 10.5, more preferably from pH8.0 to 9.5.

As an exemplary preferred embodiment, the present invention provides an oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, wherein the pH range is 7.5-11.

As an exemplary further preferred embodiment, the present invention provides an oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, wherein the pH range is 7.5-11.

As an exemplary preferred embodiment, the present invention provides an oral fruity vehicle comprising the following components: 3.5 to 13 percent (V/V) of glycerin, 2.6 to 14 percent (V/V) of sorbitol solution, 0.05 to 0.28 percent (m/V) of saccharin sodium, 0.06 to 0.45 percent (m/V) of xanthan gum, 0.6 to 2 percent (m/V) of dipotassium hydrogen phosphate, 0.3 to 1.6 percent (m/V) of sodium acetate, 0.05 to 0.15 percent (m/V) of trisodium phosphate, 0.009 to 0.16 percent (m/V) of methylparaben, 0.01 to 0.25 percent (m/V) of potassium sorbate, 0.06 to 0.15 percent (V/V) of essence, 0.07 to 0.25 percent (V/V) of pigment solution, 0.006 to 0.09 percent (m/V) of ethylenediamine tetraacetic acid sodium, 62.6 to 93.77 percent (V/V) of water, and the pH range is 7.5 to 11.0.

As an exemplary further preferred embodiment, the present invention provides an oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 1% -35% (m/V) of sucrose, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, and the pH range is 8.0-9.5.

As an exemplary further preferred embodiment, the present invention provides an oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 3% -20% (m/V) of sucrose, 0.05% -0.28% (m/V) of saccharin sodium, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of ethylenediamine tetraacetic acid sodium, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V) of pigment and 68.3% -94.94% (V/V) of water, and the pH range is 8.0-9.5.

In the solution system of the present invention, where m/V represents the mass to volume ratio, i.e. how many grams of solute are contained per milliliter of solution. V/V represents the volume percent, i.e., the ratio of the volume of liquid solute to the volume of the final solution.

The oral fruity solvent prepared by the invention is a solvent which does not contain alcohol, has fruit taste and is convenient to use. When a pharmacist prepares a temporary oral liquid medicine, the medicine can be added to make the taste better. Can be taken alone or used for flavoring aqueous solution. In addition, the compound can be combined with an oral alkaline suspension solvent to adjust the taste of the compound, so that the original suspension has fruit taste and better taste, and the physical stability of the suspension can be increased. The product contains a proper amount of buffering agent, so that the pH of the solution is kept stable, and the product is an excellent solvent which can be selected by pharmacists when preparing temporary oral liquid medicines. However, when in use, the sustained release tablets/capsules or the controlled release tablets/capsules are not crushed and dissolved in the product for use according to the specification of the medicine. Because the product is weak, if the pH value of the solution is increased, the stability of the product is reduced. The low-solubility alkaline ion medicine may be precipitated in non-ionized state, and if the medicine is prepared, the medicine should be prepared into suspension and then mixed with the suspension for use.

It is therefore another object of the present invention to provide the use of the oral alkaline suspension vehicle and/or the oral fruity vehicle prepared according to the invention for the formulation of a temporary oral liquid medicament.

The oral alkaline suspension solvent and/or fruity solvent prepared by the invention is very suitable for preparing medicines which are easy to degrade in an acidic solvent to prepare an oral suspension, wherein the medicines which are unstable under acidic conditions are selected from omeprazole, lansoprazole, rabeprazole, duloxetine, aspirin, posaconazole, ilaprazole, esomeprazole magnesium, dexlansoprazole, pantoprazole, mesalamine, diclofenac sodium, paroxetine, mycophenolate sodium, cimicosin, ibuprofen, erythromycin and the like or combinations thereof. Because of the defoamer and proper amount of preservative, the composition has mild property, has a certain buffer effect on the medicine when being matched with the medicine, and is suitable for being used by patients with dysphagia and the dosage (such as pediatric medicine) needs to be adjusted. If the tablets are added to water for administration as usual, children may be reluctant to take the aqueous solution to cause dose loss. Adding solid such as tablet, granule capsule, etc. into oral alkaline suspension solvent and/or fruit solvent, stirring to obtain suspension solution, and pouring into graduated measuring cup according to dosage to obtain liquid with comfortable taste, which is acceptable for patients. The menstruum can reasonably divide the dosage, so that the dosage of the medication for the children is accurate, and the accurate medication for the newborn infants can be realized; the medicine has good stability in the buffer solution of the solvent, quick absorption and convenient carrying, thereby reducing toxic and side effects, improving the compliance of children for medicine application and achieving the effect of quick curative effect.

The oral alkaline suspension solvent and the fruity solvent prepared by the invention can be used respectively or in combination. When the compound is used, the compound can be carried out according to the volume ratio of the oral alkaline suspension solvent to the oral fruity solvent of 9:1-1:9 (v/v), more preferably according to the volume ratio of the oral alkaline suspension solvent to the oral fruity solvent of 2:1-1:2 (v/v), and most preferably according to the volume ratio of the oral alkaline suspension solvent to the oral fruity solvent of 1:1 (v/v). The oral fruity dissolvent is mainly used for supplementing the deficiency of the oral alkaline suspension dissolvent. Therefore, the fruity vehicle can be diluted in the solution volume ratio mentioned above by adding the pre-prepared suspension vehicle, preferably according to 1:1 volume was diluted to final volume and mixed well.

Depending on the nature of the drug, different compounding methods may be used, such as:

aqueous solution: the materials are first moistened with water or other water-soluble matrix (e.g., glycerin or sorbitol), or dissolved in a minimum amount of water, and then stirred with an oral alkaline suspension vehicle.

Suspension vehicle: when used with oral alkaline suspension vehicles or other suspensions, the key is to first formulate an initial suspension and then dilute the initial suspension to the corresponding volume using a sweet vehicle. Wherein, when the composition is used together with an oral alkaline suspension vehicle, the ratio of the two is preferably approximately equal.

The oral fruity solvent and/or the oral alkaline suspension solvent prepared by the invention can prepare better suspension after almost all medicine powder or tablets are crushed into powder. Among them, in order to obtain a fine powder of the drug, the drug is preferably ground using a mortar and pestle. In preparation, less than half of the desired volume of the product is first decanted into a graduated container. And taking out a small amount of the product from the container, mixing with the medicinal powder, or mixing with the medicinal powder with a very hydrophobic material or surfactant, and grinding with a mortar and pestle to obtain a mixture with certain viscosity. During mixing, the remainder of the product was gradually added until all was added to the initial suspension. However, when in use, the sustained release tablets/capsules or the controlled release tablets/capsules are not crushed and dissolved in the product for use according to the specification of the medicine.

Compared with the existing products in the market, the oral fruity solvent and the oral alkaline suspension solvent prepared by the invention contain a proper amount of buffering agent, so that the pH of the solution is kept stable within a wider range, and the oral fruity solvent and the oral alkaline suspension solvent are suitable for more drug selection and are excellent solvents which can be selected by pharmacists when preparing temporary oral liquid drugs. The fruit-flavored solvent can be matched to adjust the taste of the oral liquid, so that the original oral liquid is endowed with fruit flavor and better in taste, and the physical stability of the oral liquid can be improved.

In summary, the technical scheme provided by the invention is summarized as follows:

1. an oral alkaline suspension vehicle composition comprising the following components: microcrystalline cellulose 0.2-2.8% (m/V), sodium carboxymethylcellulose 0.02-1.5% (m/V), xanthan gum 0.05-3.8% (m/V), carrageenan 0.05-0.6% (m/V), preservative 0.033-0.288% (m/V), buffer 0.11-11.05% (m/V), defoamer 0.01-1% (V/V) and water 99.0-99.99% (V/V), and the pH range is 7.5-11.

2. An oral alkaline suspension vehicle composition according to claim 1, characterized in that: the buffer in the oral alkaline suspension vehicle is any buffer capable of maintaining the vehicle at a pH of 7.5-11 in an aqueous state, optionally an autophosphoric acid/sodium hydroxide buffer, dipotassium hydrogen phosphate-sodium hydroxide buffer, phosphate buffer, sodium acetate buffer, or any combination thereof.

3. An oral alkaline suspension vehicle composition according to claim 2, characterized in that: the buffering agent in the oral alkaline suspension solvent is 1% -10% (m/V) of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate or any combination thereof.

4. An oral alkaline suspension vehicle composition according to claim 3, characterized in that: the buffering agent in the oral alkaline suspension solvent contains 0.01-1.5% (m/V) of sodium acetate, 0.07-9.2% (m/V) of dipotassium hydrogen phosphate and 0.03-0.35% (m/V) of trisodium phosphate.

5. An oral alkaline suspension vehicle composition according to claim 1, characterized in that: the defoamer in the oral alkaline suspension solvent is selected from emulsified silicone oil, higher alcohol fatty acid ester compound, polyoxyethylene polyoxypropylene pentaerythritol ether, polyoxyethylene polyoxypropylene alcohol amine ether, polyoxypropylene glycerol ether, polyoxypropylene polyoxyethylene glycerol ether, polydimethylsiloxane or a combination thereof.

6. The oral alkaline suspension vehicle composition according to claim 5, characterized in that: the antifoaming agent in the oral alkaline suspension solvent is polydimethylsiloxane.

7. The oral alkaline suspension vehicle composition according to claim 5, characterized in that: the content of the antifoaming agent in the oral alkaline suspension solvent is 0.01% -0.5% (V/V).

8. The oral alkaline suspension vehicle composition according to claim 7, characterized in that: the content of the antifoaming agent in the oral alkaline suspension solvent is 0.04% -0.29% (V/V).

9. The oral alkaline suspension vehicle composition according to claim 6, characterized in that: the defoamer in the oral alkaline suspension solvent is polydimethylsiloxane, and the content is 0.04% -0.29% (V/V).

10. An oral alkaline suspension vehicle composition according to claim 1, characterized in that: the preservative in the oral alkaline suspension vehicle is selected from methyl benzoate, propyl benzoate, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, calcium propionate, chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or a combination thereof.

11. An oral alkaline suspension vehicle composition according to claim 10, characterized in that: the preservative in the oral alkaline suspension solvent is potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate or a combination thereof.

12. An oral alkaline suspension vehicle composition according to claim 1, characterized in that: the preservative in the oral alkaline suspension solvent contains 0.003% -0.008% (m/V) of methylparaben and 0.03% -0.28% (m/V) of potassium sorbate.

13. An oral alkaline suspension vehicle composition according to claim 1, characterized in that: the water in the oral alkaline suspension solvent is selected from mineral water, purified water, space water or water for injection.

14. The oral alkaline suspension vehicle composition according to any one of claims 1-13, characterized in that: the oral alkaline suspension vehicle further comprises 0.04% -35% (m/V) flavoring agent.

15. The oral alkaline suspension vehicle composition according to claim 14, characterized in that: the content of the flavoring agent in the oral alkaline suspension solvent is 2% -25% (m/V).

16. The oral alkaline suspension vehicle composition according to claim 15, characterized in that: the content of the flavoring agent in the oral alkaline suspension solvent is 3% -20% (m/V).

17. The oral alkaline suspension vehicle composition according to claim 14, characterized in that: the flavoring agent in the oral alkaline suspension is selected from sucrose, fructose, maltose, lactose, starch sugar, saccharin sodium or a combination thereof.

18. The oral alkaline suspension vehicle composition according to claim 17, characterized in that: the oral alkaline suspension vehicle contains 1% -35% (m/V) sucrose.

19. The oral alkaline suspension vehicle composition according to claim 17, characterized in that: the oral alkaline suspension vehicle contains 0.04% -0.3% (m/V) sodium saccharin.

20. The oral alkaline suspension vehicle composition according to claim 17, characterized in that: the oral alkaline suspension solvent contains 3% -20% (m/V) sucrose and 0.05% -0.28% (m/V) saccharin sodium.

21. The oral alkaline suspension vehicle composition according to any one of claims 1-20, characterized in that: the pH range of the oral alkaline suspension solvent is 7.5-10.5.

22. An oral alkaline suspension vehicle composition according to claim 21, characterized in that: the pH range of the oral alkaline suspension solvent is between pH8.0 and 9.5.

23. An oral alkaline suspension vehicle composition comprising the following ingredients: microcrystalline cellulose 0.25% -1.8% (m/V), sodium carboxymethylcellulose 0.03% -1.2% (m/V), xanthan gum 0.06% -3% (m/V), carrageenan 0.06% -0.5% (m/V), sodium acetate 0.03% -1.45% (m/V), dipotassium hydrogen phosphate 0.08% -3.2% (m/V), trisodium phosphate 0.05% -0.3% (m/V), methylparaben 0.04% -0.28% (m/V), potassium sorbate 0.035% -0.28% (m/V), polydimethylsiloxane 0.05% -0.25% (V/V) and purified water 99.75% -99.95% (V/V), and the pH range is 8.0-9.5.

24. An oral alkaline suspension vehicle comprising the following ingredients: microcrystalline cellulose 0.25% -1.8% (m/V), sodium carboxymethylcellulose 0.03% -1.2% (m/V), sucrose 1% -35% (m/V), xanthan gum 0.06% -3% (m/V), carrageenan 0.06% -0.5% (m/V), sodium acetate 0.03% -1.45% (m/V), dipotassium hydrogen phosphate 0.08% -3.2% (m/V), trisodium phosphate 0.05% -0.3% (m/V), methylparaben 0.04% -0.28% (m/V), potassium sorbate 0.035% -0.28% (m/V), polydimethylsiloxane 0.05% -0.25% (V/V) and purified water 99.75% -99.95% (V/V), and the pH range is 8.0-9.5.

25. Use of an oral alkaline suspension vehicle composition according to any one of claims 1-24 for the preparation of an oral suspension of a drug susceptible to degradation in an acidic vehicle, said drug being unstable under acidic conditions selected from omeprazole, lansoprazole, rabeprazole, duloxetine, aspirin, posaconazole, ilaprazole, esomeprazole magnesium, dexlansoprazole, pantoprazole, mesalamine, diclofenac sodium, paroxetine, sodium mycophenolate, cimecoxib, ibuprofen, erythromycin or a combination thereof.

26. An oral fruity vehicle composition comprising the following components: 3-15% (V/V) of glycerin, 2-16% (V/V) of sorbitol solution, 0.04-0.5% (m/V) of xanthan gum, 0.11-11.05% (m/V) of buffering agent, 0.006-0.6% (m/V) of preservative, 0.005-0.1% (m/V) of chelating agent, 0.01-0.5% (V/V) of fruity flavoring agent and 68.5-94.99% (V/V) of water, and the pH range is 7.5-11.

27. The oral fruity vehicle composition of claim 26, wherein: the buffering agent in the oral fruity vehicle is any buffering agent capable of maintaining the vehicle at a pH of 7.5-11 in an aqueous state, optionally a self-phosphate/sodium hydroxide buffering agent, a dipotassium hydrogen phosphate-sodium hydroxide buffering agent, a phosphate buffering agent, a sodium acetate buffering agent, or any combination thereof.

28. The oral fruity vehicle composition of claim 27, wherein: the buffering agent in the oral fruity solvent is 1% -10% (m/V) of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate or any combination thereof.

29. The oral fruity vehicle composition of claim 27, wherein: the buffering agent in the oral fruity solvent contains 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate and 0.03% -0.35% (m/V) of trisodium phosphate.

30. The oral fruity vehicle composition of claim 26, wherein: the preservative in the oral fruity vehicle is selected from methyl benzoate, propyl benzoate, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, calcium propionate, chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate or a combination thereof.

31. An oral fruity vehicle composition according to claim 30, characterized in that: the preservative in the oral fruity solvent is potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate or a combination thereof.

32. An oral fruity vehicle composition according to claim 30, characterized in that: the preservative in the oral fruity solvent contains 0.001-0.2% (m/V) of methyl parahydroxybenzoate, 0.001-0.1% (m/V) of propyl parahydroxybenzoate and 0.004-0.3% (m/V) of potassium sorbate.

33. The oral fruity vehicle composition of claim 26, wherein: the fruit flavoring agent in the oral fruit solvent is natural essence selected from orange, cherry, apple, banana, strawberry, grape, lemon, melon or yogurt.

34. An oral fruity vehicle composition according to claim 33, characterized in that: the fruit flavor flavoring agent in the oral fruit flavor solvent is cherry flavor or orange flavor natural essence.

35. The oral fruity vehicle composition of claim 34, wherein: the fruit flavor flavoring agent in the oral fruit flavor solvent is cherry essence 0.05% -0.2% (V/V).

36. The oral fruity vehicle composition of claim 26, wherein: the chelating agent in the oral fruity solvent is selected from ethylenediamine tetraacetic acid (EDTA), aminotriacetic acid (NTA), diethylenetriamine pentaacetic acid, citric Acid (CA), tartaric Acid (TA), gluconic Acid (GA), hydroxyethyl ethylenediamine triacetic acid (HEDTA), dihydroxyethyl glycine (DEG) and the like.

37. The oral fruity vehicle composition of claim 36, wherein: the chelating agent in the oral fruity solvent is disodium ethylenediamine tetraacetate 0.005% -0.1% (m/V).

38. The oral fruity vehicle composition of claim 26, wherein: the water in the oral fruity solvent is selected from mineral water, purified water, space water or water for injection.

39. The oral fruity vehicle composition of any one of claims 26-38, characterized in that: the oral fruity vehicle further comprises 0.04% -35% (m/V) flavoring agent.

40. An oral fruity vehicle composition according to claim 39, characterized in that: the content of the flavoring agent in the oral fruity solvent is 2% -25% (m/V).

41. The oral fruity vehicle composition of claim 40, wherein: the content of the flavoring agent in the oral fruity solvent is 3% -20% (m/V).

42. An oral fruity vehicle composition according to claim 39, characterized in that: the flavoring agent in the oral fruity vehicle is selected from sucrose, fructose, maltose, lactose, starch sugar, saccharin sodium or a combination thereof.

43. An oral fruity vehicle composition according to claim 42, characterized in that: the oral fruity vehicle contains 1% -35% (m/V) sucrose.

44. An oral fruity vehicle composition according to claim 42, characterized in that: the oral fruity vehicle contains 0.04% -0.3% (m/V) sodium saccharin.

45. An oral fruity vehicle composition according to claim 42, characterized in that: the oral fruity vehicle contains 3-20% (m/V) sucrose and 0.05-0.28% (m/V) saccharin sodium.

46. The oral fruity vehicle composition of any one of claims 26-45, wherein: the oral fruity vehicle further comprises a pigment, wherein the pigment accounts for 0.05% -0.2% (V/V).

47. An oral fruity vehicle composition according to claim 46, characterized in that: the pigment in the oral fruity solvent accounts for 0.1% -0.15% (V/V).

48. An oral fruity vehicle composition according to claim 47, characterized in that: the oral fruity vehicle contains 0.1% -0.15% (V/V) pink pigment.

49. The oral fruity vehicle composition of any one of claims 26-48, characterized by: the pH range of the oral fruity solvent is 7.5-10.5.

50. An oral fruity vehicle composition according to claim 49, characterized in that: the pH of the oral fruity solvent is 8.0-9.5.

51. An oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, wherein the pH range is 7.5-11.

52. An oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, wherein the pH range is 7.5-11.

53. An oral fruity vehicle comprising the following components: 3.5 to 13 percent (V/V) of glycerin, 2.6 to 14 percent (V/V) of sorbitol solution, 0.05 to 0.28 percent (m/V) of saccharin sodium, 0.06 to 0.45 percent (m/V) of xanthan gum, 0.6 to 2 percent (m/V) of dipotassium hydrogen phosphate, 0.3 to 1.6 percent (m/V) of sodium acetate, 0.05 to 0.15 percent (m/V) of trisodium phosphate, 0.009 to 0.16 percent (m/V) of methylparaben, 0.01 to 0.25 percent (m/V) of potassium sorbate, 0.06 to 0.15 percent (V/V) of essence, 0.07 to 0.25 percent (V/V) of pigment solution, 0.006 to 0.09 percent (m/V) of ethylenediamine tetraacetic acid sodium, 62.6 to 93.77 percent (V/V) of water, and the pH range is 7.5 to 11.0.

54. An oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 1% -35% (m/V) of sucrose, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, and the pH range is 8.0-9.5.

55. An oral fruity vehicle comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 3% -20% (m/V) of sucrose, 0.05% -0.28% (m/V) of saccharin sodium, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of ethylenediamine tetraacetic acid sodium, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V) of pigment and 68.3% -94.94% (V/V) of water, and the pH range is 8.0-9.5.

56. Use of an oral alkaline suspension vehicle according to any one of claims 1-24 and/or an oral fruity vehicle according to any one of claims 26-55 for the preparation of a temporary oral liquid medicament.

57. The application of claim 56, wherein: the oral alkaline suspension solvent and/or fruity solvent is matched with the acidic solvent to prepare the drug which is easy to degrade in the acidic solvent to prepare the oral suspension, and the drug which is unstable under the acidic condition is selected from omeprazole, lansoprazole, rabeprazole, duloxetine, aspirin, posaconazole, ilaprazole, esomeprazole magnesium, dexlansoprazole, pantoprazole, mesalamine, diclofenac sodium, paroxetine, mycophenolate sodium, and the combination thereof.

58. The application of claim 57, wherein: the oral alkaline suspension solvent and the fruity solvent can be used separately or in combination.

59. The application of claim 56, wherein: when the medicine is matched for use, the volume ratio of the oral alkaline suspension solvent to the oral fruity solvent is 9:1-1:9 (v/v).

60. The use according to claim 59, wherein: when the compound preparation is used, the volume ratio of the oral alkaline suspension solvent to the oral fruity solvent is 2:1-1:2 (v/v).

61. The application of claim 60, wherein: when the compound preparation is used, the volume ratio of the oral alkaline suspension solvent to the oral fruity solvent is 1:1 (v/v).

Drawings

FIG. 1: stability data of omeprazole in alkaline suspension vehicle and acidic vehicle are compared. The vertical axis represents drug concentration, and the horizontal axis represents investigation time. The fold line 1 is alkaline suspension dissolvant, and the fold line 2 is acid dissolvant.

Fig. 2: stability data of ibuprofen in alkaline suspension vehicle and acidic vehicle were compared. The vertical axis represents drug concentration, and the horizontal axis represents investigation time. The fold line 1 is alkaline suspension dissolvant, and the fold line 2 is acid dissolvant.

Detailed Description

EXAMPLE 1-1 preparation of alkaline suspension vehicle

The components are as follows: microcrystalline cellulose 8g, sodium carboxymethylcellulose 0.8g, xanthan gum 2.4g, carrageenan 1.6g, methyl p-hydroxybenzoate 1g, potassium sorbate 1g, anhydrous sodium acetate 3.3g, anhydrous dipotassium hydrogen phosphate 3g, simethicone 1ml, trisodium phosphate 1.1g, propyl p-hydroxybenzoate 0,08g, potassium sorbate 1g, and purified water to 1000 ml.

The operation process comprises the following steps: the amount of each component required for the total amount of preparation was calculated, and each component was accurately weighed. 900mL of purified water was heated to 70-75deg.C. 1.0g of methylparaben, 0,08g of propylparaben and 3.3g of anhydrous sodium acetate were added and dissolved. 3g of dipotassium hydrogen phosphate is added and stirred for dissolution. 1g of potassium sorbate is added and stirred for dissolution. And (3) removing the hot water bath, and respectively adding 8g of microcrystalline cellulose, and stirring and mixing uniformly. 2.4g of xanthan gum is added and stirred for even dissolution. 1.6g of carrageenan is added and stirred for even dissolution. Adding 0.8g of sodium carboxymethyl cellulose, stirring and mixing uniformly. Stirring was continued until complete dissolution, and 1ml of simethicone was added and mixed with stirring. Purified water was added to 1000ml and stirred well. Trisodium phosphate 1.1g was added and the pH was adjusted to 8.71 and the solution was filled into plastic bottles, 100 ml/bottle.

Examples 1-2 preparation of alkaline suspension vehicles

The components are as follows: microcrystalline cellulose 7.5g, sodium carboxymethylcellulose 1.0g, xanthan gum 2.8g, carrageenan 1.5g, trisodium phosphate 0.8g, anhydrous sodium acetate 2.5g, anhydrous dipotassium hydrogen phosphate 4g, simethicone 0.5ml, methylparaben 1g, propylparaben 0,08g, potassium sorbate 1g, purified water to 1000 ml.

The operation process comprises the following steps: the amount of each component required for the total amount of preparation was calculated, and each component was accurately weighed. 900mL of purified water was heated to 70-75deg.C. 1.0g of methylparaben, 0,08g of propylparaben, 2,5g of anhydrous sodium acetate, 4g of dipotassium hydrogen phosphate and 1g of potassium sorbate are added and stirred for dissolution. The hot water bath is removed, 7.5g of microcrystalline cellulose, 2.8g of xanthan gum, 1.5g of carrageenan, 1.0g of sodium carboxymethylcellulose, 0.8g of trisodium phosphate, 0.5ml of simethicone and 1000ml of purified water are respectively added, and the mixture is stirred uniformly and has the pH of 8.6. The solution was filled into plastic bottles, 100 ml/bottle.

Examples 1-3 preparation of alkaline suspension vehicles

The components are as follows: microcrystalline cellulose 8.5g, sodium carboxymethylcellulose 0.6g, xanthan gum 2.0g, carrageenan 2.0g, anhydrous sodium acetate 2.0g, anhydrous dipotassium hydrogen phosphate 5g, simethicone 1.2ml, trisodium phosphate 1.2g, methylparaben 0,8g, propylparaben 0,05g, potassium sorbate 0.5g, purified water was added to 1000 ml.

The operation process comprises the following steps: the amount of each component required for the total amount of preparation was calculated, and each component was accurately weighed. 900mL of purified water was heated to 70-75deg.C. 0,8g of methylparaben and 0,05g of propylparaben are added and stirred for dissolution. 2.0g of anhydrous sodium acetate, 5g of dipotassium hydrogen phosphate and 0.5g of potassium sorbate. The hot water bath is removed, 8.5g of microcrystalline cellulose, 2.0g of xanthan gum, 2.0g of carrageenan and 0.6g of sodium carboxymethyl cellulose are respectively added, 0.8g of trisodium phosphate and 1.2ml of simethicone are added, purified water is added to 1000ml, and the mixture is stirred uniformly and has the pH of 8.69. The solution was filled into plastic bottles, 100 ml/bottle.

Examples 1-4 preparation of alkaline suspension vehicles

A composition; 1.5g of xanthan gum, 0.8g of sodium carboxymethyl cellulose, 1.5g of potassium sorbate, 1g of citric acid, 1ml of simethicone, 1.6 g of carrageenan, 8g of microcrystalline cellulose, 1.5g of trisodium phosphate, 0.08g of propyl p-hydroxybenzoate, 80g of sucrose, 1g of methyl p-hydroxybenzoate, 0.1g of disodium ethylenediamine tetraacetate, 15g of anhydrous dipotassium hydrogen phosphate, 10g of anhydrous sodium acetate and purified water to 1000ml.

The operation process comprises the following steps: 800ml of water was added to a stainless steel beaker and heated to 70-75 ℃.1g of methylparaben is added and stirred for dissolution. 0.08g of propyl parahydroxybenzoate was added and dissolved with stirring, and the heating furnace was turned off. 2g of xanthan gum was added (xanthan gum was slowly added and stirred until no particle cake was present). Stirring to dissolve, and stirring to dissolve 0.8g of sodium carboxymethyl cellulose. 1.6 g of carrageenan is stirred and dissolved. Microcrystalline cellulose 8g was dissolved with stirring. 15g of dipotassium hydrogen phosphate is added and stirred for dissolution. 10g of sodium acetate, 1g of citric acid, 80g of sucrose and 1ml of simethicone are added, and the mixture is stirred and dissolved. 1.5g of potassium sorbate is added and stirred for dissolution. Adding 1.5g of trisodium phosphate, stirring and dissolving, and adjusting the PH to 8.7 after the raw materials are fully stirred and dissolved uniformly. 0.1g of disodium ethylenediamine tetraacetate, 1ml of essence and 2ml of pigment solution are added. Purified water was added to 1000ml. Stirring well, pH 8.5. The solution was filled into bottles, 100 ml/bottle.

Example 2-1 preparation of alkaline fruity vehicle

The components are as follows: 81ml of glycerin, 90ml of sorbitol solution, 1.68g of xanthan gum, 10.g of anhydrous sodium acetate, 15g of anhydrous dipotassium hydrogen phosphate, 0.65g of trisodium phosphate, 0.3g of methyl parahydroxybenzoate, 0.08g of propyl parahydroxybenzoate, 1g of potassium sorbate, 0.1g of disodium edetate, 1ml of essence, 2ml of pigment solution and 1000ml of purified water.

The operation process comprises the following steps: the amount of each component required for the total amount was calculated and each component was accurately weighed. 600mL of purified water was heated to 70-75deg.C, methyl parahydroxybenzoate 0,3g, propyl parahydroxybenzoate 0,05g was added, and the mixture was stirred to dissolve. The heating furnace is removed. 81ml of glycerin, 90ml of sorbitol solution, 15g of anhydrous dipotassium hydrogen phosphate, 10g of anhydrous sodium acetate, 1g of potassium sorbate, 1.68g of xanthan gum, 0.65g of trisodium phosphate, 1ml of essence, 2ml of pigment solution, 0.1g of disodium ethylenediamine tetraacetate, and 1000ml of purified water are added, and the mixture is stirred uniformly to have the pH of 8.56. The solution was filled into plastic bottles, 100 ml/bottle.

EXAMPLE 2-2 preparation of alkaline fruity vehicle

The components are as follows: 75ml of glycerin, 95ml of sorbitol solution, 1.2g of saccharin sodium, 1.9g of xanthan gum, 12g of anhydrous sodium acetate, 18g of anhydrous dipotassium hydrogen phosphate, 0.5g of trisodium phosphate, 0.5g of methylparaben, 0.09 g of propylparaben, 1.2g of potassium sorbate, 0.15g of disodium ethylenediamine tetraacetate, 1.2ml of essence, 2.4ml of pigment solution and purified water to 1000ml.

The operation process comprises the following steps: the amount of each component required for the total amount was calculated and each component was accurately weighed. 600mL of purified water was heated to 70-75℃and 0,5g of methylparaben, 0,09g of propylparaben was added thereto and dissolved by stirring. The heating furnace is removed. 75ml of glycerin, 95ml of sorbitol solution, 1.2g of saccharin sodium, 18g of anhydrous dipotassium hydrogen phosphate, 12g of anhydrous sodium acetate, 1.2g of potassium sorbate, 1.9g of xanthan gum, 0.8g of trisodium phosphate, 1.2ml of essence and 2 of pigment solution are added. 4ml of disodium ethylenediamine tetraacetate 0.15g, purified water added to 1000ml, and stirred well, pH 8.51. The solution was filled into plastic bottles, 100 ml/bottle.

Examples 2-3 preparation of alkaline fruity vehicle

The components are as follows: 85ml of glycerin, 85ml of sorbitol solution, 0.8g of saccharin sodium, 100g of sucrose, 1.4g of xanthan gum, 9g of anhydrous sodium acetate, 12g of anhydrous dipotassium hydrogen phosphate, 0.3g of trisodium phosphate, 0.2g of methylparaben, 0.06g of propylparaben, 0.8g of potassium sorbate, 0.05g of disodium edetate, 1.8ml of essence, 1.8ml of pigment solution and purified water to 1000ml.

The operation process comprises the following steps: the amount of each component required for the total amount was calculated and each component was accurately weighed. 600mL of purified water was heated to 70-75℃and 0.2g of methylparaben and 0.06g of propylparaben were added thereto and dissolved by stirring. The heating furnace is removed. 85ml of glycerin, 85ml of sorbitol solution, 0.8g of saccharin sodium, 100g of sucrose, 12g of anhydrous dipotassium hydrogen phosphate, 9g of anhydrous sodium acetate, 0.8g of potassium sorbate, 1.4g of xanthan gum, 0.3g of trisodium phosphate, 1.8ml of essence, 1.8ml of pigment solution, 0.05g of disodium ethylenediamine tetraacetate, and 1000ml of purified water are added, and the mixture is stirred uniformly to obtain the pH of 8.82. The solution was filled into bottles, 100 ml/bottle.

Examples 2-4 preparation of alkaline fruity vehicle

A composition; 1.5g of potassium sorbate, 1.5g of xanthan gum, 1.5g of anhydrous citric acid, 200g of sucrose, 0.08g of propyl parahydroxybenzoate, 0.3g of methyl parahydroxybenzoate, 0.1g of disodium ethylenediamine tetraacetate, 15g of anhydrous dipotassium hydrogen phosphate, 10g of anhydrous sodium acetate, 1.5g of trisodium phosphate, 1ml of essence, 2ml of pigment solution and adding purified water to 1000ml.

The operation process comprises the following steps: 700ml of water was added to a stainless steel beaker and heated to 70-75 ℃. 0.3g of methylparaben is added and stirred for dissolution. 0.08g of propylparaben is added and dissolved by stirring, and the heating electric furnace is closed. 1.5g of xanthan gum is added, stirred and dissolved, and the mixture is uniformly mixed (the xanthan gum is slowly added and stirred until no particle block exists). 200g of sucrose was added and dissolved with stirring. 15g of dipotassium hydrogen phosphate is added and stirred for dissolution. 10g of sodium acetate was added thereto and dissolved by stirring. 1.5g of potassium sorbate is added and stirred for dissolution. Adding trisodium phosphate 1.5g, stirring and dissolving, and adjusting pH to 8.7 after the raw materials are fully stirred and dissolved uniformly. Disodium ethylenediamine tetraacetate 0.1g, essence 1ml, pigment solution 2ml, and purified water 1000ml were added. Stirring was uniform and the pH was 8.52. The solution was filled into bottles, 100 ml/bottle.

EXAMPLE 3 alkaline vehicle stability Studies

According to the relevant regulations of the general rule 9001 of the stability test guidelines for bulk drugs and pharmaceutical preparations and the stability study technical guidelines for chemical drugs (bulk drugs and preparations) of the four general rules of the 2015 edition of Chinese pharmacopoeia, stability studies of influence factor tests, acceleration tests and long-term tests are respectively carried out on the alkaline suspension solvents and the alkaline fruity solvents (specification 100 ml) prepared in the examples 1 and 2.

The sample is inspected according to law when the influence factor test is inspected; samples of commercially available packages were taken for testing under accelerated and long term conditions (25 ℃ + -2 ℃/60% RH+ -10% RH), and were tested as usual. Stability investigation items include properties, pH, specific gravity, viscosity. Comparing the stability examination results at different times with the results of 0 months, and comparing the stability change condition and trend of the product, the results prove that the shapes of the alkaline suspension solvent and the alkaline fruity solvent are kept stable in each examination.

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Example 4-1 preparation of omeprazole enteric-coated tablet alkaline suspension vehicle

1ml/mg of an enteric-coated tablet suspension of oral omeprazole was prepared. Firstly, uniformly stirring and mixing the alkaline suspension solvent and the alkaline fruity solvent (1:1) for later use. Grinding 5 omeprazole enteric-coated tablets into powder in a mortar, adding about 20ml of alkaline mixed solvent, stirring uniformly to form paste, adding a small amount of mixed solvent, stirring uniformly, pouring into a constant volume bottle, using the rest mixed solvent for three times, washing the mortar body, and fixing the volume to 100ml. Placing into plastic bottle, shaking, and labeling. Placing in refrigerator at 4deg.C for 2 days, 7 days, 14 days, and 30 days respectively, shaking, sampling, and detecting content according to high performance liquid chromatography of Chinese pharmacopoeia 2020.

Example 4-2 preparation of omeprazole enteric-coated tablet acid vehicle

1ml/mg omeprazole enteric-coated tablet suspension is prepared. An acidic suspension medium (microcrystalline cellulose 8g, sodium carboxymethylcellulose 0.34g, xanthan gum 2.0g, carrageenan 1.7g, calcium sulfate 0.89g, trisodium phosphate 1.0g, citric acid 2.5g, dimethicone 1ml, methylparaben 1g, potassium sorbate 1g, purified water to 1000ml, pH 4.34) was first mixed with an acidic fruity medium (glycerin 81ml, sorbitol solution 90ml, sodium saccharin 1g, xanthan gum 0.5g, citric acid 15g, sodium citrate 20g, methylparaben 0.3g, propylparaben 0.08g, potassium sorbate 1g, essence 1ml, purified water to 1000ml, pH 4.3) according to 1:1 uniformly stirring and mixing for standby. Grinding 5 omeprazole enteric-coated tablets into powder in a mortar, adding about 20ml of alkaline mixed solvent, stirring uniformly to form paste, adding a small amount of mixed solvent, stirring uniformly, pouring into a constant volume bottle, using the rest mixed solvent for three times, washing the mortar body, and fixing the volume to 100ml. Filling into plastic bottles, shaking, and labeling. Placing into refrigerator for 4 deg.C, shaking for 2 days and 7 days respectively, sampling, and detecting content according to high performance liquid chromatography of Chinese pharmacopoeia 2020.

The test data for examples 4-1 and 4-2 are shown in the following table and in FIG. 1.

Detection result: omeprazole was degraded by more than 85% in acid vehicle for 2 days, and no longer detected later.

Degradation is less than 8% in alkaline suspension solvent for 30 days, and retention rate is more than 90%.

The results show that; omeprazole is relatively stable in alkaline suspension solvents and omeprazole is unstable in acidic solvents.

Example 5-1 preparation of ibuprofen in an alkaline suspension vehicle

A suspension of 5.5ml/mg oral ibuprofen was prepared. Firstly, uniformly stirring and mixing the alkaline suspension solvent and the alkaline fruity solvent (1:1) for later use. Omeprazole 0.55 g is ground into powder in a mortar, about 20ml of alkaline mixed solvent is added to be stirred uniformly into paste, a small amount of mixed solvent is added to be stirred uniformly, the mixture is poured into a constant volume bottle, the rest mixed solvent is used for three times, the mortar body is washed clean, and the constant volume is 100ml. Placing into plastic bottle, shaking, and labeling. And (5) putting the mixture into a refrigerator for 4-DEG cold storage.

Shaking and sampling for 1,5, and 14 days respectively, and detecting content according to high performance liquid chromatography of Chinese pharmacopoeia 2020 edition.

EXAMPLE 5-2 preparation of ibuprofen acid vehicle

A suspension of 5.5ml/mg ibuprofen was prepared. An acidic suspension medium (microcrystalline cellulose 8g, sodium carboxymethylcellulose 0.34g, xanthan gum 2.0g, carrageenan 1.7g, calcium sulfate 0.89g, trisodium phosphate 1.0g, citric acid 2.5g, dimethicone 1ml, methylparaben 1g, potassium sorbate 1g, purified water to 1000ml, pH 4.34) was first mixed with an acidic fruity medium (glycerin 81ml, sorbitol solution 90ml, sodium saccharin 1g, xanthan gum 0.5g, citric acid 15g, sodium citrate 20g, methylparaben 0.3g, propylparaben 0.08g, potassium sorbate 1g, essence 1ml, purified water to 1000ml, pH 4.3) according to 1:1 uniformly stirring and mixing for standby. 0.55 g of ibuprofen is ground into powder in a mortar, about 20ml of acid mixed solvent is added to be stirred uniformly into paste, a small amount of mixed solvent is added to be stirred uniformly, the mixture is poured into a constant volume bottle, the rest mixed solvent is used for three times, the mortar body is washed clean, and the constant volume is 100ml. Placing into plastic bottle, shaking, and labeling. And (5) putting the mixture into a refrigerator for 4-DEG cold storage.

Shaking and sampling respectively for 1,5 days, and detecting content according to high performance liquid chromatography of Chinese pharmacopoeia 2020 edition.

The test data for examples 5-1 and 2-2 are shown in the following table and FIG. 2.

Detection result: ibuprofen is degraded by more than 35% in acid solvent for 5 days, and is no longer detected later. Degradation is less than 4% in an alkaline suspension solvent for 14 days, and the retention rate is more than 96%.

The results show that: ibuprofen is relatively stable in alkaline suspension vehicles and unstable in acidic vehicles.

Claims

2. The oral alkaline suspension vehicle composition of claim 1, wherein: the oral alkaline suspension vehicle further comprises 0.04% -35% (m/V) flavoring agent.

3. An oral alkaline suspension vehicle composition comprising the following ingredients: microcrystalline cellulose 0.25% -1.8% (m/V), sodium carboxymethylcellulose 0.03% -1.2% (m/V), xanthan gum 0.06% -3% (m/V), carrageenan 0.06% -0.5% (m/V), sodium acetate 0.03% -1.45% (m/V), dipotassium hydrogen phosphate 0.08% -3.2% (m/V), trisodium phosphate 0.05% -0.3% (m/V), methylparaben 0.04% -0.28% (m/V), potassium sorbate 0.035% -0.28% (m/V), polydimethylsiloxane 0.05% -0.25% (V/V) and purified water 99.75% -99.95% (V/V), and the pH range is 8.0-9.5.

4. An oral alkaline suspension vehicle composition comprising the following ingredients: microcrystalline cellulose 0.25% -1.8% (m/V), sodium carboxymethylcellulose 0.03% -1.2% (m/V), sucrose 1% -35% (m/V), xanthan gum 0.06% -3% (m/V), carrageenan 0.06% -0.5% (m/V), sodium acetate 0.03% -1.45% (m/V), dipotassium hydrogen phosphate 0.08% -3.2% (m/V), trisodium phosphate 0.05% -0.3% (m/V), methylparaben 0.04% -0.28% (m/V), potassium sorbate 0.035% -0.28% (m/V), polydimethylsiloxane 0.05% -0.25% (V/V) and purified water 99.75% -99.95% (V/V), and the pH range is 8.0-9.5.

5. An oral fruity vehicle composition comprising the following components: 3-15% (V/V) of glycerin, 2-16% (V/V) of sorbitol solution, 0.04-0.5% (m/V) of xanthan gum, 0.11-11.05% (m/V) of buffering agent, 0.006-0.6% (m/V) of preservative, 0.005-0.1% (m/V) of chelating agent, 0.01-0.5% (V/V) of fruity flavoring agent and 68.5-94.99% (V/V) of water, and the pH range is 7.5-11.

6. The oral fruity vehicle composition of claim 5, wherein: the oral fruity vehicle further comprises 0.04% -35% (m/V) flavoring agent.

7. The oral fruity vehicle composition of claim 5, wherein: the oral fruity vehicle further comprises a pigment, wherein the pigment accounts for 0.05% -0.2% (V/V).

8. An oral fruity vehicle composition comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, wherein the pH range is 7.5-11.

9. An oral fruity vehicle composition comprising the following components: 3% -15% (V/V) of glycerin, 2% -16% (V/V) of sorbitol solution, 1% -35% (m/V) of sucrose, 0.04% -0.5% (m/V) of xanthan gum, 0.01% -1.5% (m/V) of sodium acetate, 0.07% -9.2% (m/V) of dipotassium hydrogen phosphate, 0.03% -0.35% (m/V) of trisodium phosphate, 0.001% -0.2% (m/V) of methylparaben, 0.001% -0.1% (m/V) of propylparaben, 0.004% -0.3% (m/V) of potassium sorbate, 0.005% -0.1% (m/V) of sodium ethylenediamine tetraacetate, 0.01% -0.5% (V/V) of essence, 0.05% -0.2% (V/V) of pigment and 68.3% -94.94% (V/V) of water, and the pH range is 8.0-9.5.

10. Use of an oral alkaline suspension vehicle composition according to any one of claims 1-4 and/or an oral fruity vehicle composition according to any one of claims 5-9 for the formulation of a temporary oral liquid medicament.