WO2012102538A2

WO2012102538A2 - Dry syrup composition

Info

Publication number: WO2012102538A2
Application number: PCT/KR2012/000565
Authority: WO
Inventors: 최재영; 진광미
Original assignee: 제이더블유중외제약 주식회사
Priority date: 2011-01-28
Filing date: 2012-01-20
Publication date: 2012-08-02
Also published as: TW201306876A; WO2012102538A3; KR20120087723A

Abstract

Provided are: a dry syrup comprising a pharmaceutically active substance, starch and a thixotropic thickener; and a production method therefor. The dry syrup composition is advantageous in that it is rapidly hydrated and changes to an appropriate viscosity range when brought into contact with water, and so weighing and/or dosing convenience is improved and gelatinized starch is broken down inside the mouth such that viscosity is reduced and an easy-to-swallow formulation is possible.

Description

【Specification】

[Name of invention]

Dry Syrup Composition

The present invention relates to a dry syrup composition comprising a pharmacologically active substance, starch, and thixotropic thickener and a method for preparing the same.

Background Art

Pharmaceutical preparations for oral administration are mostly used in the form of solids including tablets and capsules and liquids containing syrups, elixirs, suspensions and the like. In the case of solids, it is difficult for children, the elderly, and those who have difficulty swallowing, so that oral solutions are used to improve the medication compliance of patients and to increase the absorption rate of the drug in the body. Developed.

However, oral solutions have the same problems in terms of pharmaceutical stability and ease of administration, both pharmaceutical and pharmacologically. In other words, the suspension may cause problems in the stability of the formulation, such as caking and sedimentation during storage, and in the case of syrups, due to the low viscosity and physical force exerted on the measuring device (spoon, etc.) At this time, there is a risk of drug leakage from the metering device, which makes it difficult to accurately measure and / or take doses. In particular, in patients with motility disorders (hand shake due to tremor, tremors, lack of micromotor control) or pediatric patients who are afraid of taking the drug, measuring and / or taking the correct dose using a measuring instrument This was very difficult.

In order to solve this problem, various studies on high viscosity semi-solid preparations using gels have been conducted. However, most of the developed formulations have high viscosity, which makes it difficult to distribute the main medicine uniformly to the base using high energy during the manufacturing process, and due to the limitation of the transferable viscosity range, the container is compressed to discharge the dosage. If physical There is a problem such as the need for a large amount of external force, or a special container capable of measuring the exact amount. In addition, the semi-solid composition has a problem that the manufacturing process is complicated and requires high energy due to the high viscosity characteristics.

Therefore, the formulation instability of the low-viscosity formulations such as liquid formulations and problems of release from the device during taking and / or quantification, the difficulty of accurate measurement of high-viscosity formulations such as semi-solid formulations, uneven distribution of the active substance, and difficulty swallowing There is a need for the development of formulations that can solve the problem. [Detailed Description of the Invention]

[Technical problem]

Pharmaceutical preparations for oral administration are mostly used in the form of solids including tablets and capsules and liquids containing syrups, elixirs, suspensions and the like. In the case of solids, it is difficult for children, the elderly, and those who have difficulty swallowing, and thus, the oral solution is used to improve the patient's medication rate and to increase the absorption rate of the drug by improving this problem. Was developed.

However, oral solution may cause problems with the stability of the pharmaceutical and pharmacological stability, and has the same problem in the administration of convenience, ^"that is, for a suspension separation layer during storage of the formulation (caking, sedimentation), such as formulation, In the case of syrups, due to the low viscosity and physical force exerted on the measuring device (spoon, etc.), there is a risk of drug leakage from the measuring device during weighing and oral administration, making it difficult to accurately measure and / or take the dose. There is. In particular, in patients with motility disorders (shakes due to tremors, hand hydration, lack of micromotor control) or pediatric patients who are afraid of taking medications, accurate metering and / or It was very difficult.

In order to solve this problem, various studies on high viscosity semi-solid preparations using gelol have been conducted. However, most of the formulations developed have high viscosities that allow the use of high energy during the manufacturing process to uniformly dispense the main drug into the base. In addition to the inconvenience of distributing, due to the limitations of the transferable viscosity range, when the container is compressed and the dose is released, a large amount of external force is required, or a special container capable of measuring the exact amount is required. there are ^"problems of that. In addition, the semi-solid composition has a problem in that the manufacturing process is complicated and requires high energy due to the high viscosity characteristics.

Therefore, the formulation instability of the low-viscosity formulations such as liquid formulations and problems with the discharge from the instrument during taking and / or quantification, difficulty in accurate measurement of high-viscosity formulations such as semi-solid formulations, uneven distribution of the active substance, and difficulty swallowing There is a need for the development of formulations that can solve the problem.

[Measures of problem]

In order to achieve the above object, one embodiment of the present invention provides a dry syrup composition comprising a pharmacologically active substance, starch, and thixotropic thickener. The dry syrup composition is characterized in that it is used in combination with water at the time of use.

As used herein, 'dry syrup' is formulated in the form of dry powder or dry granules, and means a preparation in a form taken in combination with water when taken. As used herein, the term 'dry syrup composition' is used to mean a dry syrup form and preparation comprising a pharmacologically active substance, starch, and thixotropic thickener.

As used herein, the term 'dry syrup hydration composition' is used to mean a dry syrup composition in which water is mixed with the dry syrup composition when the dry syrup composition is used.

In the present invention, 'hydration' means mixed with water.

Dry syrup compositions are prepared, packaged, stored, and distributed in dry syrup form and are used in combination with water when taken by an individual user. Therefore, the manufacturing process is simpler and the volume is smaller, compared to the formulations that are mixed with the existing water and packed, stored and distributed in hydrated form _. It is easy to store and transport and has the advantage of low risk of denaturation of ingredients as it is stored and distributed in dry form. At this time, the amount of water mixed at the time of administration can be appropriately adjusted according to the type of pharmacologically active substance included, and in general, 40% (w / v) to 99¾ (w / v) of the total amount of dry syrup composition mixed with water. Preferably, 60% (w / v) to 95% (w / v), but is not limited thereto, and may be appropriately adjusted according to the amount of additives such as active materials and binders.

The dry syrup composition according to the present invention is hydrated when mixed with water to increase the viscosity, and is characterized by a rapid change in a range easy to take. If the viscosity of the formulation is too low, it is difficult to take it because it is discharged from the dosing device during preparation.However, if the viscosity is too high, sufficient hydration does not occur, swallowing is difficult, the dissolution rate of the active ingredient is decreased, and workability is poor during manufacture. Has a problem. The present invention essentially includes starch as a thixotropic thickener contained in the dry syrup, and by adjusting its content range, the dry syrup composition has a viscosity that can solve all of the above problems when mixed with water and at the same time hydrated. It improves the ease of taking by improving the speed (hydration power), and in the oral cavity is broken down by the action of saliva is characterized in that the viscosity is lowered to facilitate swallowing.

Therefore, the dried syrup composition of the present invention essentially uses starch as a thixotropic thickener, and when mixed with water, has excellent hydration power, and quickly changes to a sufficiently high viscosity to facilitate taking, while salivary administration of oral administration Degradation by amylase action, the viscosity is lowered to change to a sufficiently low viscosity to facilitate swallowing, there is an advantage that it is possible to meet both ease of taking and ease of swallowing. In addition, the dry syrup composition of the present invention has an excellent hydration rate and hydration power at which the viscosity after 1 minute of hydration reaches about 80% or more, preferably 90¾ or more of the viscosity after 60 minutes, thereby reducing the preparation preparation time and reducing the convenience of taking. Can be further enhanced.

Since the effect of the use of the starch desired in the present invention is obtained when the dry syrup composition is mixed with water when used and hydrated, in order to achieve the above effect, the range of starch content in the dry syrup composition mixed with water during use is important. Therefore, the content of the components of the dry syrup composition, including starch The ranges are expressed based on the total weight of the dry syrup composition with water mixed in use.

Starch used in the present invention is at least one general starch selected from the group consisting of corn starch, tapioca starch, potato starch, sweet potato starch, wheat starch, brown root starch, taro starch and the like; Modified starch obtained by oxidation, graft or enzymatic treatment of the general starch; And it may be one or more selected from the group consisting of gelatinized starch of the general starch, in particular gelatinized starch is good.

Pregelatinized starch (P-starch) is also known as alpha starch, and the above-mentioned general starch is heated with water (for example, 8 ⁽ until rc to locrc until the water content is less than the first 15%). Heating), a swelling agent such as calcium nitrate or sodium hydroxide, or esterified or etherified by treatment with, for example, POCI _3. For example, the gelatinized starch has a water content of 5 to 15% by weight, The particle size may be 150 μιιι or less, such as, but not limited to, 0.1 to 150 μηι Starch in a dry syrup composition in a state in which it is mixed with water, in order to obtain a beneficial effect by containing starch, as described above. To achieve this effect, the starch content in the dry syrup composition should be adjusted to dry water Amount of 0.1 to 10% by weight, preferably 0.3 to 9% by weight, more preferably 0.5 to 8% by weight, more preferably 0.5 to 5% by weight and most preferably 1 to 3% by weight, based on the total amount of rub compositions When the composition is in contact with water, the viscosity of the starch is rapidly increased to a convenient range for taking, and the content of starch is 0.1% by weight or more, so that it decomposes in the mouth and decreases to a suitable range for swallowing. Preferably it is 0.3 weight ¾ or more, more preferably 0.5 weight or more, and more preferably 1% by weight or more.In addition, too much starch content increases the viscosity of the formulation itself, so that hydration does not occur well in contact with water. Since the dissolution rate of the active ingredient may be lowered, the starch content is 10% by weight or less, preferably 9% by weight or less, more preferably 8 wt%, more preferably at most 5% by weight or less, preferably preferably 3 wt% or less. The composition of the present invention comprises thixotropic thickeners other than starch. Thixotropic thickeners are thixotropic and can be used as long as they are biocompatible and capable of acting as thickeners, such as agar, carrageenan, lostbean gum and carboxymethylcellose. ， Combination of microcrystalline cellulose and carboxymethyl cellulose, colloidal silicon dioxide, Xanthan gum, Gel lan gum, dextrin, gelatin, guar gum gum), Magnesium Aluminum Silicate, polyethylene oxide, polyvinylpyridone, vinyl pyridone polymer, carboxyvinyl polymer, carboxypolymethylene, povidone, bigum, tragacanth, bentonite, methylcellulose , Polyethylene glycol and the like can be used in combination of one or more selected from the group consisting of one or two or more.

The amount of thixotropic thickener other than the starch is in the range of 0.01 to 10 weight ^< ¾, preferably 0.01 to 5 weight%, more preferably 0.1 to 2 weight% based on the total amount of dry syrup composition in which water is mixed. May be included. When the content of the thixotropic thickener other than the starch is in the above range, the composition exhibits an appropriate range of viscosity and high hydration power when in contact with water, thereby contributing more to the prevention of spillage from the metering device and ease of taking.

In addition, in order to obtain appropriate thixotropy upon contact with water, the thixotropic thickener is preferably in the range of pH 3 to 8, including weakly acidic, neutral and weakly basic.

In the composition of the present invention, the active substance means a substance that is pharmacologically or therapeutically active, and there is no particular limitation as long as it is effective in treating a disease by oral administration. One or more active substances known in the art to be effective can be determined and appropriately selected by those skilled in the art.

For example, the active substance may include analgesics, nonsteroidal anti-inflammatory drugs, antihistamines, cough suppressants, expectorants, bronchodilators, anti-infective agents, and CNS active drugs. , Cardiovascular drugs, antitumor agents, Cholesterol-lowering drugs, ant i-emet ics, vitamins, mineral complements, fecal softners, antihypertensives, antifungals, antidiabetics, ant idiabetes, amino acids ， Heart failure treatment, anemia treatment, vitamins, probiotics, herbal extracts, etc. may be used one or more selected from the group consisting of, but is not necessarily limited thereto.

More specifically, acetaminophen, ibuprofen, dexibuprofen, aspirin, diphenhydramine, valsar tan, monteleukast, scopolamine ( scopolamine zaltoprofen, tramadol, tramadol, diclofenac, aceclofenac, etodolac, piroxicam, nimesulide, celecoxib Glucosamine, zolmitriptan, alendronic acid, risedreonic acid, S-carboxymethyl cysteine, dextromethorphan, guai Guaifenesin, pseudoephedrine, phenylephrine, loratadine, ephedrine, cetirizine, mizolasin t ine, olopatadine, epinastine, procaterol, acety 1 cys tein, er dos tein, theophylline, formo Formoterol, zipeprol, difemerine, tizanidine, tiropramide, diazepam, alprazolam, buspirone, ethynyl midazolam (etizolam), risperidone (risperidone), olanzapine (olanzapine), amino sulpiride ₍₃ ^ ₅₁₁ 1 ^ 36), the claw US plastic Min (clomipramine), chlor plastic margin (chlorpromazine), ^{'rivastigmine} (rivastigmine ), Donepezil, gal ant amine, entacapone, memantine, ropinirole, selegi 1 ine, carbidopa , Levodopa, terfenadine, Ranitidine, ciprofloxacin, triazolam, terbinaf ine fluconazole, itraconazole, ketoconazole, vorconazole, voriconazole proprano proprano ), Lovastatin, simvastatin, atorvastatin atorvastatin pitavastatin, rosuvastatin, pravastatin, fenofibrate, fenofibrate, ezetimibe, ezetimibe, Cetin (f 1 uoxet ine), enalapril, irbesartan, losarartan, lamipril, nicorandil, doxazosin, Carvedi lol, diltiazem, tropisetron, ondansetron, mecl izine, azacetron, dolasetron. (dolasetron), granisetron, metformin, glimepiride, gl iclazide ^' , mitiglinide, gl ibenclamide, repaglinide (repagHnide), DL-methionine, I-valine, L-isoleucine, I-threonine, I-tryptophan, ubidecarenone (01 ^ (1 ^ 61101), tocopherol, ferric hydroxide ^■ polymaltose double salt ( Ferric hydroxide 一 polymaltose com lex, Ferrous Fumarate, folic acid, pyridoxine hydrochloride, ginseng extract, red ginseng extract, ascorbic acid, iboflavin, taamine, cyanocobalamine ( Cyanocobalamine), texpanthenol (dexpanthenol), lactic acid bacteria (Bacillus coagulans, Clostridium butyricum, etc.), and pharmaceutically acceptable salts or esters thereof, and the like may be used.

The content of the pharmacologically active substance is not particularly limited, and may be appropriately determined by a person skilled in the art in consideration of specific types of diseases, symptoms, binders, thickeners, and the like used, for example, with respect to the total amount of dry syrup composition in which water is mixed. It may be included in the range of 0.001 to 20% by weight.

The dry syrup composition of the present invention may further comprise a binder. The binder may be appropriately selected from solvents or insoluble solvents capable of appropriately dissolving or suspending the above substances in consideration of specific kinds of active substances and thickeners. Specifically, the binder may be a linear or branched alcohol having 1 to 4 carbon atoms such as purified water, glycerin, ethanol, polypropylene glycol, polyethylene glycol, a copolymer of polypropylene glycol and polyethylene glycol, sorbitol, malty, and the like. It may be one or more selected from the group consisting of, but is not necessarily limited thereto.

In the dry syrup composition of the present invention, since the liquid component (binding solvent) such as purified water and alcohol is removed during drying, the binder included in the final formulation is glycerin, polypropylene glycol, polyethylene glycol, polypropylene glycol and polyethylene. It may be at least one selected from the group consisting of a copolymer of glycol, sorbitol, polyol such as maltitol and the like.

The content of the binder may range from 0.001 to 10% by weight, preferably from 0.001 to 5% by weight, more preferably from 0.001 to 2% by weight, based on the total amount of dry syrup composition mixed with water.

In an embodiment of the present invention, the dried syrup composition comprises 0.001 to 20 parts by weight of the pharmacologically active substance; 0.1 to 10 parts by weight of starch, preferably 0.3 to .9 parts by weight, more preferably 0.5 to 8 parts by weight, still more preferably 0.5 to 5 parts by weight, most preferably 1 to 3 parts by weight; 0.01 to 10 parts by weight, preferably 0.01 to 5 parts by weight, more preferably 0.1 to 2 parts by weight; And 0.001 to 10 parts by weight of the binder, preferably 0.001 to 5 parts by weight, more preferably 0.001 to 2 parts by weight, and may be characterized in that water is mixed and used at the time of use. The amount of water mixed at this time is 40% (w / v) to 99¾> (w / v), preferably 60% (w / v) to 95% (w / v) of the total amount of dry syrup composition Can be.

In another aspect, the dry syrup composition may be provided as a dry syrup hydrating composition in which water is mixed in use. The dry syrup hydrating composition comprises 0.001 to 20% (w / v) pharmacologically active substance; 0.1 to 10 3/4 (w / v) starch, Preferably 0.3 to 9% (w / v), more preferably 0.5 to 8% (w / v), more preferably ₅ to 5% (w / v), most preferably 1 to 3% (w / v); thixotropic thickener 0.01 to 10 3/4 (w / v), preferably 0.01 to 5% (w / v), more preferably 0.1 to 2 (w / v); binder 0.001 to 10 ¾) (w / v), preferably 0.001 to 5% (w / v), more preferably 0.001 to 2% ( _w / v); and 40 to 99% (w / v) water, preferably 60 to 95¾> (w / v).

On the other hand, the dry syrup composition according to the present invention may further include one or more additives selected from the group consisting of sweeteners, fragrances, organic acids, preservatives, excipients and the like commonly used in the art in a conventional content range.

For example, the dry syrup composition according to the present invention may further comprise a sweetener and / or a fragrance in order to mask the bitter taste of the pharmacologically active substance. In this way, when the sweetener and the appropriate fragrance of fruit flavor with high palatability of the child are added, the bitter taste of the pharmacologically active substance may be completely shielded to increase the swelling dose of the pediatric patient. In addition, in the case of using a predetermined sweetener, it can be administered to patients with diabetes by preventing dental caries and not affecting the blood glucose content when taking the composition of the present invention. The sweetener can be used without limitation, those commonly used in the art, but preferably do not cause tooth decay, malty, sorbita (Sorbitol), Xylitol (Iylalt), etc. Sugar alcohols, stevithenes, aspartame, acesulfame, saccharin, saccharin, saccharin, saccharin, sucralose, sucrose, etc. Can be used individually or in mixture of 2 or more types, respectively. The fragrance may be used without limitation, those commonly used in the art, preferably selected from the group consisting of chocolate, strawberry, lemon, orange, grape, vanilla, cherry and apple flavors 1 or more types can be used.

These sweeteners and fragrances may be included in the range of 0.001 to 20 weight ¾> with respect to the total amount of dry syrup composition in which water is mixed when used. It is not limited.

In addition, in the present invention, in order to mask the bitter taste of the pharmacologically active substance used, it is also possible to apply the pharmaceutical masking technique commonly used in the art to the pharmacologically active substance. For example, the pharmacologically active substance may be coated with a biomolecular polymer, made into a solid dispersion, or encapsulated, but is not necessarily limited thereto. At this time, the biomolecular polymer coating, solid dispersion preparation, encapsulation, etc. may be performed according to a method known in the art.

Furthermore, the dry syrup composition of the present invention may further include an organic acid to adjust the pH, and to further increase the patient's medications. The addition of organic acids provides convenience in taking since the viscosity of the composition itself can be further lowered by promoting saliva secretion of the patient after oral administration.

Organic acids usable in the present invention include, for example, citric acid, ascorbic acid, palmitic acid, tartaric acid, and pharmaceutically acceptable salts thereof. One or more selected from the group consisting of, but is not necessarily limited thereto. Such organic acids may be included in the range of 0.001 to 5% by weight based on the total amount of dry syrup composition in which water is mixed when used, but is not limited thereto.

In addition, other excipients such as preservatives, and / or suspending agents, solubilizing agents, buffers, and the like may be appropriately selected and added by those skilled in the art depending on the use and occasions. You can choose to.

In addition, the dry syrup composition of the present invention may be stored in a storage container that can be transferred to a measuring instrument such as a spoon, and may be individually packaged in a single dose. At this time, the storage container may be used without limitation as long as it is commonly used for storage or packaging of the pharmaceutical composition.

The dry syrup composition of the present invention uses a mixture of water at the time of use, the amount of the water is as described above, dry syrup for ease of use The amount of water added to the storage container containing the composition is indicated, and water can be added to the indicated area. As such, the dry syrup composition in which water is mixed is hydrated to have a state of viscosity, and in this state, when a physical force applied to shake the container is applied, the viscosity decreases to reach the equilibrium viscosity, and thus the discharge from the container and the spoon It is easy to transfer to the weighing container, and accurate weighing is possible by sufficient spreadability in the weighing container such as spoon. In addition, after being weighed on a measuring vessel such as a spoon, when it is left in an idle state, the viscosity increases as the initial viscosity is reached again, and thus has an outflow resistance that does not fall from the measuring vessel.

The dry syrup composition of the present invention has a very good hydration power of 80% or more, preferably 90% or more, more preferably 95¾> or more, when mixed with water when used, in terms of viscosity after 1 minute of hydration compared to viscosity after 60 minutes of hydration. There is an advantage.

The dry syrup composition of the present invention can be prepared by a simple process of mixing, coalescing, drying and formulation.

More specifically, the method for producing a dry syrup composition of the present invention comprises the steps of mixing the active ingredient, starch, thixotropic thickener; And

Drying and sizing the obtained mixture

It may include.

In an embodiment of the present invention, the preparation method may further comprise the step of mixing by adding a binder to the obtained mixture after the step of mixing the active ingredient, starch, thixotropic thickener.

The type and content of the active ingredient, starch and thixotropic thickener are as described above. For example, 0.01 to 20 parts by weight of the pharmacologically active substance; 0.1 to 10 parts by weight of starch, preferably 0.3 to 9 parts by weight, more preferably 0.5 to 8 parts by weight, still more preferably 0.5 to 5 parts by weight, most preferably 1 to 3 parts by weight; 0.01 to 10 parts by weight, preferably 0.01 to 5 parts by weight, more preferably 0.1 to 2 parts by weight of a thixotropic thickener; And, when a binder is used, 0.001 to 10 parts by weight of the binder, preferably 0.001 to 5 parts by weight, more preferably 0.001 to 2 parts by weight may be used. The drying step may be performed until the content of the solvent (eg, the binder solvent) in the composition is 0.5% by weight or less, but is not limited thereto. In the case of adding other excipients such as sweeteners, fragrances, organic acids, and preservatives, suspending agents, solubilizers, laxatives, etc. to the dry syrup composition, all the active ingredients, starch, thixotropic thickeners are added Can be mixed.

In the preparation of a dry syrup containing an existing thickener, in many cases, to increase the rate of hydration is to perform a process of grinding the thickener. However, in the preparation of the dry syrup composition of the present invention, by using starch as a thixotropic thickener, it is possible to achieve a high hydration rate without grinding the thickener. Therefore, the dry syrup composition manufacturing method of the present invention is characterized in that it does not include a grinding process of the thickener, it is possible to manufacture a more convenient and economical dry syrup composition due to this feature.

[Effects of the Invention]

As described in detail above, the dry syrup composition of the present invention includes starch and one or more thixotropic thickeners in an appropriate range, and is quickly hydrated upon contact with water to change to an appropriate viscosity range, thereby making it easy to measure and / or take Starch breaks down in the mouth, reducing the viscosity to provide a swallowing-friendly formulation. In addition, the dry syrup composition of the present invention has the advantage that the viscosity of the granules before drying can be prepared in a simple process, economical and excellent workability. [Specific contents to carry out invention]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these are only for illustrating the present invention, and the scope of the present invention is not limited by these examples. Example 1 Preparation of Ibuprofen Dry Syrup Composition I and Measurement of Hydration 1.1. Preparation of Ibuprofen Dry Syrup Composition

Ibuprofen (BASF), gellan gum (CPkelco), xanthan gum (DANISCO), starch (p-starch, (potato starch, DMV)), preservative (methylparaben (E.Merck, butyl) in purified water Paraben E.Merck), citric acid (citric acid anhydrateJAKURI), sodium citrate (Sodium citrate 2H ₂ 0, YAKURI), fragrance (strawberry CT3501, COSIS and lemon L20056, COSIS), and sweeteners (Xili, (RQUETTE), sucral Rhodes (Tate & lyle), Steviten (Dapyeong), and Aspartame (ANHUI WANHE) were added and combined in the amounts shown in Table 1. The mixing was performed for 10 minutes using a Double cone mixer (A 402, Erweka). (A) Using a Planetary mixer (AR402, Erweka), ethanol and poloxamer 407 (BASF) were added to the obtained mixture in the amounts shown in Table 1 below and mixed (B). It was granulated using (16 mesh, Daishin Machine).

The granules obtained were dried (50 ° C., 3 hours) using a tray dryer (LT-100, Freund). The dried material was established using an oscillator. Water was added to the obtained sieved material and ibuprofen epidermal granules and mixed in a double cone mixer for 10 minutes to prepare a dry syrup composition (Examples 1-1 to 1-5) mainly containing ibuprofen in the form of a dry powder. The dried granules prepared were put into purified water 100 ml before use.

For comparison, ibuprofen dry syrup compositionol was prepared in the same manner as described above except that starch (p-starch) was not added.

The composition of the formulation is summarized in Table 1 below.

[Table 1]

Example 1-1 Example 1-2 Example 1-3 Example 1-4 Example 1-5 Comparative Example 1 Ibuprofen 2.00 2.00 2.00 2.00 2.00 2.00 Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized Starch 0.5 2.0 5.0 8.0 10.0

Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaban 0.02 0.02 0.02 0.02 0.02 0.02 Citric acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 0.2. Xyllet 10.0 10.0 10.0 10.0 10.0 10.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

(Unit: g)

1.2. Hydration Characteristics of Ibuprofen Dry Syrup Composition

In order to measure the hydration rate of the ibuprofen dry syrup composition prepared in Examples JL-1 to 1-5 and Comparative Example 1, the viscosity was measured after 1 minute, after 5 minutes, and after 60 minutes, and after ₆₀ minutes of hydration. Hydration was measured by measuring the viscosity after 1 min of hydration (hydration power (¾>) = (viscosity after 1 min of hydration / viscosity after 60 minutes of hydration) * 100). The hydration is hydrated by adding water to a dry syrup composition of 2.0 g equivalent of ibuprofen so that the total volume is 100 mL, and the viscosity is No. of Brookfield visosmeter (DV-II). The measurement was carried out using 64 spindles, and the viscosity measurement conditions were measured at a rotational speed of 50 rpm, quality temperature, and 10 seconds after the start of the measurement.

The obtained results are shown in Table 2 below.

Table 2

(Viscosity unit: cps, hydration unit:%)

Viscosity after 60 minutes Hydration 2,500 3,000 4,000 4,800 5,500 2,300 ('Equilibrium Viscosity)

Hydration (92.00 93.33 93.75 91.67 83.64 73.91 1 minute)

* Equilibrium viscosity: measured after shaking the container 20 times

** Initial Viscosity: Measured with the Container Left

As shown in Table 2, Comparative Example 1, which does not use P-starch, has a slower viscosity increase after time of hydration, which means that the hydration of the granules is delayed or not partially hydrated. This results in a problem of drug content uniformity because the granules do not stick to the container wall or are evenly suspended in the actual dose. To improve this problem, as in Examples 1-1 to 1-5, gelatinized starch was used in an amount of 0.5 to 10% by weight based on the total amount of the composition after hydration, and with other thixotropic thickeners (gellan gum, xanthan gum, etc.). As a synergistic effect, when water is added, the viscosity after 1 minute is 80% or more of the viscosity after 60 minutes, especially when the content of gelatinized starch is 0.5 to 8% by weight, the viscosity after 1 minute represents 90% or more of the viscosity after 60 minutes, It can be seen that it shows a very fast hydration rate. Example 2: Preparation of Ibuprofen Dry Syrup Composition II and Dissolution Rate Measurement 2.1. Preparation of Ibuprofen Dry Syrup Composition

In the same manner as in Example 1.1, the ibuprofen dry syrup composition (Examples 2-1 to 2-5) was prepared using the composition of Table 3 below, and for the sake of comparison, the formulation of Comparative Example 2 which did not use gelatinized starch. Was prepared.

TABLE 3

Example 2 Example 1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Comparative Example 2 Ibuprofen 2.00 2.00 2.00 2.00 2.00 2.00 Carrageenan 0.4 0.4 0.4 0.4 0.4 0.4 Xanthan Gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized Starch 0.5 2.0 5.0 8.0 10.0-Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Manntle 10.0 10.0 10.0 10.0 10.0 10.0 Sucralo 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Stevitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

(Unit: g)

2.2. Ibuprofen Dry Syrup Composition

For the ibuprofen dry syrup composition prepared in Examples 2-1 to 2-5 and Comparative Example 2, the dissolution rate by the paddle method (50 rpm, 60 minutes, pH 7.2 eluate) was measured, and the hydration rate of hydration was measured. In order to measure the viscosity after 1 minute, after 5 minutes and after 60 minutes, the equilibrium viscosity and initial viscosity after 60 minutes of hydration were measured in the same manner as in Example 1.2.

The obtained results are shown in Table 4 below.

Table 4

As shown in Table 4, no gelatinized starch was used for comparison. In Comparative Example 2, due to the high viscosity, the water permeation is not smooth during dissolution, it can be seen that the dissolution rate is only 64%, so that the dissolution rate is not shown. However, all of the formulations of Examples 2-1 to 2-5 containing 0.5 to 10% by weight of the total amount of the composition after hydration showed a high dissolution rate of 75% or more, especially the gelatinized starch content of 0.5 to 10% by weight. In the case of 8 weight ¾ (Examples 2-1 to 2-4), it can be seen that the dissolution rate standard of 80% or more defined in the USP standard is satisfied. Example 3: Preparation III of Ibuprofen Dry Syrup Composition III and Residual Determination 3.1. Preparation of Ibuprofen Dry Syrup Composition

Ibuprofen dry syrup compositions (Examples 3-1 to 3-5) were prepared using the composition of Table 5 below in the same manner as in Example 1.1, and for comparison, the formulation of Comparative Example 3, which did not use gelatinized starch. Was prepared.

Table 5

Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

(Unit: g)

3.2. Residual Determination of Ibuprofen Dry Syrup Composition

In order to measure the residual feeling in the mouth when taking the ibuprofen dry syrup composition prepared in Examples 3-1 to 3-5 and Comparative Example 3, the viscosity (equilibrium viscosity) after hydration 60 minutes and the viscosity after 5 mastications were measured. The degree of liver change was measured. Latency after 60 minutes of hydration was measured as in Example 1.2, and the viscosity after 5 mastications was also measured as in Example 1.2.

The obtained results are shown in Table 6 below.

Table 6

Viscosity change rate (¾;) = {(viscosity after 60 minutes of hydration -viscosity after 5 times wetting) / viscosity after 60 minutes of hydration) * 100}

As shown in Table 6, for comparison, Comparative Example 3, which did not use gelatinized starch, showed that the viscosity decrease was almost 10% or less before and after mastication, which was due to viscosity. It means that a feeling of residual in the mouth may remain. On the other hand, the formulations of Examples 3-1 to 3-5 containing gelatinized starch, because the gelatinized starch contained as a thickening agent, as well as serves to sharply lower the viscosity as amylopectin is hydrolyzed by amylase in the mouth when taken. ， The degree of viscosity decrease after 5 mastications is remarkable, and the lowered viscosity in the mouth facilitates the thirsty of the preparation to enhance the ease of taking. Example 3-1 to Comparative Example 3 The rate of change in viscosity after 5 mastications of the formulation of 3-5 is about 2-6 fold _. Increased. However, in the case of Example 3-5 containing the gelatinized starch in an amount of 10% by weight relative to the total amount of the composition after hydration, there was a tendency that the hydrate was not sufficiently hydrated due to the high viscosity. Example 4 Preparation of Glucosamine Dry Syrup Composition and Measurement of Spreadability

4.1. Preparation of Glucosamine Dry Syrup Composition

A glucosamine dry syrup composition (Examples 4-1 to 4-5) was prepared in the same manner as in Example 1.1, except that glucosamine was used as a main component, using the composition of Table 7 below. The formulation of Comparative Example 4 was prepared without using starch.

[Table 7]

Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

(Unit: g)

4.2. SpreadabiHty Determination of Glucosamine Dry Syrup Composition Spreadability is a major factor that enables quantitative use of drugs with fast hydration when weighed into a spoon in a container. In order to measure the spreadability of the glucosamine dry syrup composition prepared in Examples 4-1 to 4-5 and Comparative Example 4, the mass deviation (RSD, ¾) was measured in a spoon. The difference in mass is shown.

Inversion time is a measure of the time it takes for a formulation to fall to the floor by flipping the spoon within 10 seconds after spreading the formulation onto a spoon.

The obtained results are shown in Table 8 below.

Table 8

As shown in Table 8, the formulations of Examples 4-1 to 4-5 containing gelatinized starch in an amount of 0.5 to 10% by weight based on the total amount of the composition after hydration have a mass deviation of about 5% compared to the formulation of Comparative Example 4. 4 times reduced, it can be seen that it is more advantageous for the dosage. However, in the case of Example 4-5 containing 10 wt% of gelatinized starch, there was a tendency of not being fully hydrated due to the high viscosity. Examples 5-12: Preparation and Thixotropy Determination of Dry Syrup Compositions of Various Drugs

Preparation of Dry Syrup Compositions of Various Drugs

Its main ingredient is itraconazole, ondansetron, metformin, dexibuprofen, Itraconazole dry syrup composition (Examples 5-1 to 5-5, Table 9) in the same manner as in Example 1.1, except for using glucosamine, glymepiride, or cetirizine, using the composition of Tables 9 to 16 below. ), Ranitidine dry syrup composition (Examples 6-1 to 6-5, Table 10), silver dansetron dry syrup composition (Examples 7-1 to 7-5, Table 11), metformin dry ^' syrup composition (Example

8-1 to 8-5, Table 12), dexibuprofen dry syrup composition (Examples 9-1 to

9-5, Table 13), Glucosamine dry syrup composition (Examples 10-1 to 10-5, Table 14), Glymepirid dry syrup composition (Examples 11-1 to 11-5, Table 15), and cetirizine dry A syrup composition (Examples 12-1 to 12-5, Table 16) was prepared, and for comparison, the formulations of Comparative Examples 6-12 were prepared without the use of gelatinized starch.

Table 9

Itraconazole Preparation (Unit: g)

Table 10

Ranitidine formulation (unit: g)

Example 6-1 Example 6-2 Example 6-3 Example 6-4 Example 6-5 Comparative Example 6 Ranitidine 0.15 0.15 0.15 0.15 0.15 0.15 Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized Starch 0.5 2.0 5.0 8.0 10.0-Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xyllet 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 11

Ondansetron preparation (unit: g) ^''

Example 7-1 Example 7-2 Example 7-3 Example 7-4 Example 7-5 Comparative Example 7 Ondansetron 0.04 0.04 0.04 0.04 0.04 0.04 Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized Starch 0.5 2.0 5.0 8.0 10.0- Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Re & L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xylitol 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 12

Metformin preparation (unit: g)

Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 ^' 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 13

Dexibuprofen Formulation (Unit: g)

Table 14

Glucosamine preparations (unit: g)

¾ Lan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized starch 0.5 2.0 5.0 8.0 10.0-Methyl paraben 0.08 0.08 0.08 0.08 0.08 0.08 Butyl paraben 0.02 0.02 0.02 0.02 0.02 0.02 Citric acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xyllet 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Steviten 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

TABLE 15

Glymepiride Formulation (Unit: g)

Example Example Example Example Example Comparative Example 11 11-1 11-2 11—3 11-4 11-5

Glymepiride 0.02 0.02 0.02 0.02 0.02 0.02 Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized starch 0.5 2.0 5.0 8.0 10.0-Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xylyl 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 16

Cetirizine preparations in g

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Example 12 12-1 12-2 12-3 12-4 12-5

Cetirizine 0.1 0.1 0.1 0.1 0.1 0.1 Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatin starch ^' 0.5 2.0 5.0 8.0 10.0-Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xyllet 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Steviten 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 ^• 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL Thixotropy measurement of dry syrup composition of various drugs

The thixotropy of the dry syrup compositions of various drugs prepared in Examples 5-1 to 12-5 was measured and compared with the respective comparative examples.

Specifically, by the method described in Example 1.2, the viscosity (equilibrium viscosity and initial viscosity) after 1 minute, 5 minutes and 60 minutes after hydration was measured, and the viscosity after 1 minute of hydration compared to the viscosity after 60 minutes of hydration was measured. (Hydraulic power (¾ = (viscosity after 1 minute of hydration / viscosity after 60 minutes of hydration) * 100). Also, the dissolution rate of each of the above formulations was measured. The dissolution rate measurement conditions of each drug were as follows. 17-24), and the mass deviation and inversion time at the spoon were measured by the method described in Example 4.1.

The obtained results are shown in Tables 17 to 24 below.

Table 17

Thixotropic properties of itraconazole formulations

Inversion

More than 3 minutes More than 3 minutes More than 3 minutes More than 3 minutes More than 3 minutes Less than 30 seconds t ime

Dissolution rate: pH 6.8 phosphate buffer, 900 ml, 50 rpm

Table 18

Thixotropy of ranitidine formulations

* Dissolution rate: 0.1N HC1, 900 ml, 50 rpm paddle method

Table 19

Thixotropy of ondansetron preparations

Example 7-1 Example 2 Example 7-3 Example 7-4 Example 7 一 5 Comparative Example 7 After 1 minute of hydration

2,300 2,800 3,700 4,500 4,500 1,800 Viscosity (cps)

5 minutes after hydration

2,400 2,900 3,850 4,550 4,700 2,100 Viscosity (cps) 60 minutes after hydration

Viscosity (cps) 2,450 3,000 4,000 4,600 5,300 2,300 (Equilibrium viscosity)

60 minutes after hydration

Viscosity (cps) 5,800 6,000 6,600 7,700 8,500 5,600

(Initial viscosity)

Hydration (60 minutes)

93.88 93.33 92.50 97.83 84.91 78.26 ratio 1 minute

Elution rate '98.11 98.99 99.46 97.12 80.07 88.45 Mass deviation 2.10 2.63 2.37 2.44 4.55 6.97

Inversion

* Dissolution rate: water, 500 ml, 50 rpm paddle method

Table 20

Thixotropy of metformin preparations

Example 8-1 Example 8-2 Example 8-3 Example 8-4 Example 8-5 Comparative Example 8 1 minute after hydration

2,350 2,750 3,750 4,450 4,700 1,900 Viscosity (cps)

5 minutes after hydration

2, 400 2,800 3,800 4,500 4,800 2, 150 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2,450 3 ， 050 3 ， 900 4,600 5,400 2,300

(Equilibrium Viscosity)

60 minutes after hydration

Viscosity (cps) 5,750 6,000 6,500 7,700 8,600 5,500 (Initial viscosity)

Hydration (60 minutes)

95.92 90.16 96.15 96.74 87.04 82.61 Ratio 1 minute viscosity)

Dissolution Rate ^* 98.68 99.05 98.43 96.00 84.21 85.78 Mass Deviation 2.46 2.10 2.22 2.98 5.79 6.01 Inversion

Dissolution rate: pH 6.8 phosphate buffer, 900 ml, 50 rpm

Table 21

Thixotropy of dexibuprofen formulation

Example 9-1 Example 9-2 Example 9-3 Example 9-4 Example 9-5 Comparative Example 9 1 minute after hydration

2,300 2，800 3,700 4,450 4,650 1,800 Viscosity (cps)

5 minutes after hydration

2,400 2,900 3,800 4,550 4,800 2,050 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2,400 3,000 3,900 4,600 5,400 2,300 (Equilibrium viscosity)

60 minutes after hydration

Viscosity (cps) 5,700 6,000 6,500 7,500 8,600 5,600 (Initial viscosity)

Hydration (60 minutes)

95.83 93.33 94.87 96.74 86.11 78.26 ratio 1 minute

Dissolution Rate ^* 95.23 94.22 96.06 92.33 87.36 85.50 Mass Deviation 2.60 2.77 2.44 2.96 6.20 5.33

Inversion

* Elution: pH 7.2 phosphate buffer, 900 ml, 50 rpm paddle method [Table 22]

Thixotropy of glucosamine preparations

Example Example Example Example Example Comparative Example 10 10-1 10-2 10-3 10-4 10-5

1 minute after hydration

2,300 2,750 3,700 4,400 4,600 1,850 Viscosity (cps)

Sign Language. After 5 minutes 2 ， 400 2,800 3,800 4,550 4,800 2,050 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2, 400 3,050 3,900 4,600 5,500 2,300

(Equilibrium Viscosity)

60 minutes after hydration

Viscosity (cps) 5,700 6,100 6,500 7,500 8, 500 5,500

(Initial viscosity)

Hydration (60 minutes)

95.83 96.36 94.87 95.65 83.64 80.43 ratio 1 minute

Dissolution Rate '' 94.05-98.16 96.97 95.33 80.06 87.75 Mass Deviation 2.31 1.90 2.94 1.77 5.06 6.08

Inversion

* Dissolution rate: water, 900 ml, 50 rpm paddle method

Table 23

Thixotropy of the glimepiride formulation

Example Example Example Example Example Example Comparative Example 11 11-1 11-2 11-3 11-4 11-5

1 minute after hydration

2,350 2,800 3,700 4,300 4,700 1,800 Viscosity (cps)

5 minutes after hydration

2,400 2,900 3,800 4,550 4,800 2,000 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2,450 3,000 3,850 4,600 5,500 2,300 (Equilibrium viscosity)

60 minutes after hydration

Viscosity (cps) 5,700 6,100 6,500 7,400 8,600 5,500

(Initial viscosity)

Hydration (60 minutes)

95.92 93.33 96.10 93.48 85.45 78.26 ratio 1 minute Dissolution Rate 96.52 95.10 96.24 93.46 88.13 84.94 Mass Deviation 2.77 1.20 2.36 2.55 5.88 6.65

Inversion

* Dissolution rate: water, 900 ml, 50 rpm paddle method

Table 24

Thixotropy of cetirizine preparations

* Dissolution rate: pH 1.2 eluent, 900 ml, 50 rpm paddle method As can be seen in Tables 17 to 24 above, regardless of the type of drug, including the gelatinized starch in an amount of 0.5 to 10% by weight relative to the total amount of the composition after hydration The formulations of Examples 5-1 to 12-5 do not contain gelatinized starch It was confirmed to hydrate at a high rate and maintain thixotropy as compared with Comparative Examples 5 to 12. However, when the content of gelatinized starch is 10% by weight, there was a tendency that it was not sufficiently hydrated due to the high viscosity. Examples 13-20: Preparation and Thixotropy Determination of a Dry Syrup Composition Comprising Two or More Drugs

Preparation of Syrup Formulations Including Various Two or More Drugs

According to the method of Example 1.1 was prepared a dry syrup composition (Examples 13-1 to 20-5) of a combination formulation containing two or more drugs with the composition shown in Tables 25 to 32 below, for comparison, The formulation of Comparative Examples 13-20 which did not use gelatinized starch was prepared.

Table 25

Complex preparations containing Ubidecarenone (unit: g)

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Examples 13-1 13-2 13—3 13-4 13-5 13 Ubidecarenone 0.1 0.1 0.1 0.1 0.1-0.1 Tocopheracetate 0.3 0.3 0.3 0.3 0.3 0.3 Riboflavin Sodium 0.05 0.05 0.05 0.05 0.05 0.05 Phosphate

Pyridoxine 0.5 0.5 0.5 0.5 0.5 0.5 hydrochloride

Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized starch 0.5 2.0 5.0 8.0 10.0

Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xyllet 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethane 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified Water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 26

Complex preparations containing ferric hydroxide-polymaltose complex (unit: g)

Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL ^' To lOOmL To lOOmL To lOOmL

Table 27

Complex formulation containing extract of Heungsam ethane (Red Ginseng fluid ethanol ext.) (Unit: g)

Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xylyl 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 28

Complex preparations containing DL-methionine (unit: g)

Example Example Example Example Example Comparative Example

16-1 16-2 16-3 16-4 16-5 16

DL-Methionine 0.09 0.09 0.09 0.09 0.09 0.09

I-valine 0.05 0.05 0.05 0.05 0.05 0.05

L-isoleucine 0.05 0.05 0.05 0.05 0.05 0.05

I-threonine 0.05 0.05 0.05 0.05 0.05 0.05

I-Tryptophan 0.05 0.05 0.05 0.05 0.05 0.05 Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized starch 0.5 2.0 5.0 8.0 10.0-Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4. 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xyllet 10.0- 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 29

Complex preparations containing valsartan (unit: g)

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Example 17-1 17-2 17-3 17-4 17-5 17 Valsartan 0.4 0.4 0.4 0.4 0.4 0.4 Pitavastatin 0.02 0.02 0.02 0.02 0.02 0.02

¾ Rangum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan Gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized Starch 0.5 2.0 5.0 8.0 10.0-Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xyllet 10.0 10.0 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 30

Complex preparations containing Bacillus coagulans (unit: g)

Example Example Example Example Example Comparative Example 18-1 18-2 18-3 18-4 18-5 18

Baci 1 lus coagulans 2.5 2.5 2.5 2.5 2.5 2.5

Clostridium 0.3 0.3 0.3 0.3 0.3 0.3 butyricum

Gelan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized starch 0.5 2.0 5.0 8.0 10.0-. Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xyllet 10.0 10.0. 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 31

Complex Formulations Containing Metformin (Unit: g)

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Examples 19-1 19-2 19-3 19-4 19-5 19 Metformin 5.0 5.0 5.0 5.0 5.0 5.0 Glymepiride 0.02 0.02 0.02 0.02 0.02 0.02 Gellan gum 0.5 0.5 0.5 0.5 0.5 0.5 Xanthan Gum 0.8 0.8 0.8 0.8 0.8 0.8 Gelatinized Starch 0.5 2.0 5.0 8.0 10.0 Methylparaben 0.08 0.08 0.08 0.08 0.08 0.08 Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid ^' 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xylitol 10.0 10.0. 10.0 10.0 10.0 6.0 Sucralose 0.1 0.1 0.1 0.1 0.1 0.1 Stebitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 ^■ 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL

Table 32

Complex preparations containing iron fumarate (unit: g)

Butylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Citric Acid 0.25 0.25 0.25 0.25 0.25 0.25 Sodium Citrate 0.15 0.15 0.15 0.15 0.15 0.15 Strawberry CT3501 0.4 0.4 0.4 0.4 0.4 0.4 Lemon L20056 0.2 0.2 0.2 0.2 0.2 0.2 Xylyl 10.0 10.0 10.0 10.0 10.0 6.0 Sucralo 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Stevitene 0.07 0.07 0.07 0.07 0.07 0.07 Aspartame 0.07 0.07 0.07 0.07 0.07 0.07 Ethanol 0.5 0.5 0.5 0.5 0.5 0.5 Poloxamer 407 0.1 0.1 0.1 0.1 0.1 0.1 Purified water To lOOmL To lOOmL To lOOmL To lOOmL To lOOmL To lOmL thixotropy measurement of dry syrup compositions of various drugs

The thixotropy of the dry syrup compositions of various complex formulations prepared in Examples 13-1 to 20-5 was measured and compared with the respective comparative examples.

Specifically, by the method described in Example 1.2, the viscosity (equilibrium viscosity and initial viscosity) after 1 minute, 5 minutes and 60 minutes of hydration was measured, and the viscosity after 1 minute of hydration compared to the viscosity after 60 minutes of hydration was measured. (Hydration power (%) = (viscosity after 1 minute of hydration / viscosity after 60 minutes of hydration) * 100). In addition, by the method described in Example 4.1, the mass deviation and inversion time at the spoon were measured.

The obtained results are shown in Tables 33 to 40 below.

Table 33

Thixotropy of complex preparations containing Ubidecarenone

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Example 13-1 13-2 13-3 13-4 13-5 13 After 1 minute of hydration

2,250 2,750 3,600 4,300 4,600 1,850 Viscosity (cps)

After 5 minutes of hydration 2,400 2,800 3,700 4,450 4,700 2,000 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2,450 ^• 3,050 3,800 4,500 5,400 2,300

(Equilibrium Viscosity)

60 minutes after hydration

Viscosity (cps) 5,300 6,100 6,400 7，350 8,500 5,400

(Initial viscosity)

Hydration (60 minutes)

91.84 90.16 94.74 95.56 85.19 80.43 Ratio 1 minute viscosity)

Mass deviation 2.33 2.34 2.71 2.99 6.77 6.51

Inversion

Table 34

Thixotropy of a complex formulation comprising ferric hydroxide-polymaltose complex

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Example 14-1 14-2 14-3 14-4 14-5 14 After 1 minute of hydration

2,200 2,850 3,600 4,300 4,600 1,900 Viscosity (cps)

5 minutes after hydration

2,400 2,950 3,750 4,550 4,800 2,100 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2,400 3,050 3，800 4,500 5，400 2,350

(Equilibrium Viscosity)

60 minutes after hydration

Viscosity (cps) 5,800 6,000 6,300 7,400 8,500 5,500 (Initial viscosity)

Hydration (60 minutes)

91.67 93.44 94.74 95.56 85.19 80.85 ratio 1 minute viscosity)

Mass deviation 2.09 2.07 2.58 2.20 5.74 7.28 Inversion

Table 35

Thixotropy of a complex formulation containing Red Ginseng fluid ethanol ext.

60 minutes after hydration

Viscosity (cps) 2,450 3,000 3,800 4,600 5,400 2 ， 350

(Equilibrium Viscosity)

60 minutes after hydration

Viscosity (cps) 5,800 6,000 6,400 7,300 8,500 5,600 (Initial viscosity)

Hydration (60 minutes)

93.88 93.33 97.37 95.65 .85.19 76.60 ratio 1 minute viscosity)

Mass deviation 2.11 2.61 2.09 2.88 6.52 7.44

Inversion

Table 37

Thixotropy of a complex formulation comprising valsartan

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Example 17-1 17-2 17-3 17-4 17-5 17 After 1 minute of hydration

2,300 2,850 3,750 4,300 4,600 1,700 Viscosity (cps)

5 minutes after hydration

2,400 2,950 3,800 4,400 4,700 2,100 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2,500 3 ， 050 3,900 4,500 5,400 2,300 (Equilibrium viscosity)

60 minutes after hydration

Viscosity (cps) 5,850 6, 050 6,400 7,400 8,650 5,500 (Initial viscosity)

Hydration (60 minutes)

92.00 93.44 96.15 95.56 85.19 73.91 ratio 1 minute viscosity)

Mass deviation. 2.34 2.23 2.74 2.99 6.57 8.51

Inversion

More than 3 minutes More than 3 minutes More than 3 minutes More than 3 minutes More than 3 minutes Less than 30 seconds t ime Table 38

Thixotropy of complex preparations containing Bacillus coagulans

Table 39

Thixotropy of the combination formulation containing metformin

EXAMPLES EXAMPLES EXAMPLES EXAMPLES EXAMPLES Comparative Example 19-1 19-2 19-3 19-4 19-5 19 After 1 minute of hydration

2,300 2,800 3,650 4,300 4,600 _. 1,800 viscosity (cps)

5 minutes after hydration

2,400 2,900 3,750 4,550 4,700 2,100 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2, 450 3,000 3,800 4, 600 5,400 2,300 (Equilibrium viscosity) 60 minutes after hydration

Viscosity (cps) 5,700 6,100 6,400 7,450 8,600 5,600

(Initial viscosity)

Hydration (60 minutes)

93.88 93.33 96.05 93.48 85.19 78.26 ratio 1 minute

Mass deviation 2.50 2.15 2.07 2.55 6.00 6.68

Inversion

More than 3 minutes More than 3 minutes More than 3 minutes More than 3 minutes More than 3 minutes Less than 30 seconds time

Table 40

Thixotropy of a complex formulation comprising iron fumarate

Example Example Example Example Example Comparative Example

20-1 20-2 20-3 20-4 20-5 20 After 1 minute of hydration

2,250 2,750 3,700 4,450 4,550 1,700 Viscosity (cps)

5 minutes after hydration

2,400 2,800 3,700 4,550 4,700 2,050 Viscosity (cps)

60 minutes after hydration

Viscosity (cps) 2, 400 3,050 3,800 4,600 5,400 2,300

(Equilibrium Viscosity)

60 minutes after hydration

Viscosity (cps) 5,800 5,900 6,400 7，400 8,650 5,650

(Initial viscosity)

Hydration (60 minutes)

93.75 90.16 97.37 96.74 84.26 73.91 Ratio 1 minute viscosity)

Mass deviation 1.91 2.44 2.81 2.33 5.22 6.80

Inversion

As can be seen in Tables 33 to 40, the formulations of Examples 13-1 to 20-5 containing gelatinized starch in an amount of 0.5 to 10% by weight based on the total amount of the composition after hydration regardless of the type of the composite formulation were gelatinized. Not contain starch At a faster rate compared to Comparative Examples 13-20. It has been found to hydrate and retain thixotropy. However, when the content of gelatinized starch is 10% by weight, there was a tendency that it was not sufficiently hydrated due to the high viscosity.

Claims

[Patent Claims]

[Claim 1]

In the form of dry syrup containing pharmacologically active substance, starch, thixotropic thickener,

When used, it is used by mixing water.

The starch content is 0.1 to 10% by weight based on the total amount of water mixed composition when used,

Dry syrup composition.

[Claim 2]

The method of claim 1,

The starch is at least one general starch selected from the group consisting of corn starch, tapioca starch, potato starch, sweet potato starch, wheat starch, carp starch, and taro starch; Modified starch of the general starch; And one or more selected from the group consisting of gelatinized starch of the general starch,

Dry syrup composition.

[Claim 3]

_According to claim 2,

The starch is a luxury starch of one or more general starches selected from the group consisting of corn starch, tapioca starch, potato starch, sweet potato starch, wheat starch, carp starch, and taro starch.

Dry syrup composition.

[Claim 4]

The method of claim 1,

The content of the starch is 0.5 to 8 weight ¾> based on the total amount of water mixed composition when used,

Dry syrup composition.

[Claim 5]

The method of claim 1,

The thixotropic thickener includes agar, carrageenan, lost bean gum, carboxymethyl cellulose, microcrystalline cellulose and carboxymethyl salose. Complex, colloidal silicon dioxide, xanthan gum, gellan gum, dextrin, gelatin, guar gum, magnesium aluminum silicate, polyethylene oxide, polyvinylpyrrolidone, vinyl pyrrolidone polymer, carboxyvinyl polymer, carboxypolymethylene, povidone, At least one selected from the group consisting of acetonitrile, tragacanth, bentonite, methylsalose, and polyethylene glycol,

Dry syrup composition.

[Claim 6]

The method of claim 1,

The content of the thixotropic thickener is 0.01 to 10% by weight based on the total amount of water mixed composition when used,

Dry syrup composition.

[Claim 7]

The method of claim 1,

Dry syrup composition, characterized in that it further comprises a binder.

[Claim 8]

The method of claim 7, wherein

The amount of the binder is 0.001 to 10% by weight, based on the total amount of water mixed composition in use,

Dry syrup composition.

[Claim 9]

0.001 to 20 parts by weight of the pharmacologically active substance; 0.1 to 10 parts by weight of starch; And 0.01 to 10 parts by weight of a thixotropic thickener,

Used in combination with water at the time of use,

Dry syrup composition.

[Claim 10]

The method according to any one of claims 1 to 9,

Further comprising at least one selected from the group consisting of sweeteners, fragrances, organic acids, preservatives, and excipients,

Dry syrup composition.