KR20040016202A - The composition and method for masking bitter taste of hydrocortisone oral preparations - Google Patents

Abstract

PURPOSE: Provided are an oral pharmaceutical composition of hydrocortisone of which bitter taste is effectively masked and a method for manufacturing the same. The composition maintains bitter taste masking system even when suspended. CONSTITUTION: An oral pharmaceutical composition of hydrocortisone comprises 1 part by weight of hydrocortisone, 0.1-2.0 part by weight of monostearate as a main masking matter and 0.05-1.0 part by weight of a sweetener as an auxiliary masking matter. Its bitter taste is effectively masked. It is formulated into powder, granules, capsules, suspension or dried syrup.

Description

The composition and method for masking bitter taste of hydrocortisone oral preparations}

The present invention relates to a hydrocortisone oral pharmaceutical composition having a bitter taste and a method for preparing the same, and more particularly, a non-ionic and solubilizing agent as a main shielding material in a pharmaceutical composition containing hydrocortisone as an active drug. By adding a certain amount of stabilizer glyceryl monostearate to adsorb glyceryl monostearate to hydrocortisone to reduce the surface area of hydrocortisone, significantly reduce the bitter taste felt when taken orally, and then add a certain amount of sweetener as an auxiliary shielding material. Hydrocortisone oral pharmaceutical composition that masks the residual bitterness of hydrocortisone, which is very bitter and inconvenient to take oral, or which is easily rejected by drugs, greatly improving the convenience of taking Manufacturing method A.

Hydrocortisone has the fewest side effects among many oral steroid drugs, and has a strong pharmacological effect as an adrenal cortex hormone. Thus, hydrocortisone is orally administered 10-120 mg / day and 1-4 times as hydrocortisone. 5 milligrams, 10 milligrams and 20 milligrams, characterized by a very low amount of active ingredient per unit formulation, does not significantly affect the formulation formally, and formulations and single doses allow effective shielding systems even with small amounts of shielding material. It has the features of the award. Hydrocortisone is produced in the middle of the adrenal cortex and has a molecular structure similar to aldosterone. In addition to affecting sugars, hydrocortisone is also involved in protein and fat metabolism and is used as an anti-inflammatory agent in many tissue lineages. An important action of hydrocortisone is to promote the action of fatty acids from adipose tissue to increase the use of fatty acids as energy sources, to reduce the use of sugars, to exhibit anti-stress action against stress such as surgery, and to suppress inflammation by suppressing immune responses. Eliminate and show anti-allergic action. Due to these advantages, it is widely used in children, but the bitter taste is very strong, there is a problem that it is difficult to administer due to the objection of the drug in children when the powder is administered. Therefore, in the present invention, the primary purpose is to effectively mask the bitter taste of hydrocortisone.

In general, the formulation of the drug is prepared to be suitable for application to the human body. In particular, orally administered drugs are commercially available in various formulations, such as tablets, capsules, powders, granules, liquids, etc., which are designed to overcome the disadvantages of drugs and to be suitable for administration. However, in some cases, it is necessary to change the properties of the drug due to the constraints of the formulation, there is a limit in the selection of the formulation to overcome the disadvantages of the drug. For example, children or elderly people who have difficulty taking tablets or capsules may be easier to take with granules or powders, but if the taste of the drug is very irritating, powders or granules prepared by the usual methods may be It does not form a proper formulation because it exposes the taste as it is. In such cases it is desirable to mask the irritating taste of the drug and then formulate it into tablets, powders or granules.

U.S. Patent No. 5,707,646 discloses a method of formulating a dry syrup by concealing bitter taste by mixing it with Eudragit egg (R) and tooth (E) having a melting point of macrolide antibiotics having a strong bitterness of 40 to 120 ° C. Is disclosed. Eudragit eggs (R) and (E) are soluble in acidic or weakly acidic conditions and water is permeable in neutral to alkaline acids. Suspending dry syrup in water causes the drug's bitter taste to elapse. As a result, the bitterness shielding effect disappears. Dry syrup prepared by this method can be said to have the effect of bitterness only when suspended immediately after suspension in water because of this disadvantage.

U. S. Patent 5,728, 403 discloses a bitter masking system consisting of a three component system of metronidazole, triglyceride mixtures and cationic copolymers. In the present invention, the melting point of the triglyceride mixture is characterized by melting at body temperature and dissolving the used polymer at low acidity so that the drug is eluted from acidic gastric juice. In the case of the present invention, the shielding effect is excellent in the solid state, but there is a problem that the bitterness shielding effect is significantly reduced when dissolved in syrup or taken in water.

U.S. Patent No. 5,405,617 discloses a technique for masking the bitter taste of a drug by using a stearyl stearate as a fatty acid ester, but the scope of the drug applied is limited to antihistamines, anti-inflammatory analgesics, anti-diabetic agents and the like.

U. S. Patent No. 5,156, 842 discloses a method of suspending antibiotics such as penicillin, erythromycin, roxithromycin and amoxicillin using a nonaqueous oil as a carrier. The purpose of this technique is to increase the bioavailability of the antibiotics used and to control the release of the drug, which is far from the object of the present invention.

British Patent Publication No. 2,081,092 discloses a pharmaceutical composition prepared by mixing waxes, fatty acid esters, and various water-soluble polymers and a manufacturing method to mask the taste of water-soluble drugs such as talampicillin hydrochloride, indenolol hydrochloride, and hydralazine hydrochloride. have. This method is limited to water-soluble drugs, and the used polymer is also water-soluble, which has a problem in that the taste masking effect is reduced when applied to the liquid.

In addition, Korean Patent Publication No. 99-86232 discloses an oral pharmaceutical composition in which the bitter taste of roxithromycin is masked by adding at least one fatty acid ester or wax having a melting point of 40 to 120 ° C. and a water-soluble or water-insoluble high molecular material. Although the preparation method is disclosed, there is a problem in delaying the drug expression due to the lowered dissolution rate per unit time, and also masks 150 mg gram titer (adult basis) of roxysomycin per unit dosage in weight ratio, which is a characteristic of the formulation. In order to do this, excessive doses have to be used, in which case there are problems in the provision of pharmaceutical drugs and inefficiency in the process.

In particular, in order to increase the convenience of taking oral drugs applied to children, oral solids, which are generally provided, may be powdered and suspended or dissolved in tasty syrups. In this case, even if the formulation masks the unpleasant taste of the drug, there is an example in which the modification of the formulation occurs in the syrup and the original unpleasant taste is reproduced as it is.

Although hydrocortisone has little side effects and is useful as a steroid-based antibiotic, there are limitations in preparing oral medications with its natural bitter taste. Therefore, the present inventors do not use any organic solvents and have a low melting point of 56 to 58 ° C. After hydrocortisone is adsorbed and powdered with reel monostearate, the sweetener is mixed with another shielding material together with a water-soluble or non-aqueous excipient to maintain the surface area of hydrocortisone by adsorption between the compositions while maintaining the pharmacological effects of hydrocortisone. The present invention was completed by recognizing that the bitter taste can be significantly reduced by reducing the bitterness.

Accordingly, the present invention is a taste masking system of a hydrocortisone formulation which does not change the formulation even when it is mixed with a general syrup or a liquid formulation, and improves the bitter taste of hydrocortisone, and thus conventional oral solid preparations such as tablets, capsules, powders, and granules. It is an object of the present invention to provide a pharmaceutical composition of a new composition that can be formulated in the formulation of and a method for preparing the same.

The present invention provides a bitter taste masked hydrocortisone oral pharmaceutical composition containing 1 part by weight of hydrocortisone, 0.1 to 2.0 parts by weight of glyceryl monostearate as a main shielding material, and 0.05 to 1.0 parts by weight of sweetener as an auxiliary shielding material. It is done.

The present invention melts glyceryl monostearate at a temperature of 58-60 ° C., adds hydrocortisone to dissolve it, adsorbs hydrocortisone to glyceryl monostearate, cools and solidifies it, and then powders it. A method for preparing a hydrocortisone oral pharmaceutical composition in which a bitter taste is mixed with a sweetener is further characterized.

Referring to the present invention in more detail as follows.

The present invention is characterized by using a physical method using adsorption, not chemical bonding between the composition to mask the bitter taste while maintaining the pharmacological effect of the active ingredient hydrocortisone. That is, a certain amount of glyceryl monostearate is used as the main shielding material to adsorb hydrocortisone to reduce the surface area of the hydrocortisone to reduce bitter taste, and a certain amount of sweetener as an auxiliary shielding material to shield the remaining bitter taste of hydrocortisone.

The pharmaceutical composition of the present invention having the above characteristics contains 1 part by weight of hydrocortisone, an adrenal cortex hormone, as an effective drug, and 0.1 to 2.0 parts by weight of glyceryl monostearate is adsorbed on hydrocortisone to mask the bitterness of hydrocortisone. And as a shielding material, 0.05-1.0 weight part of sweeteners are added and mixed. In addition to the hydrocortisone effective drug and bitter masking substance, the pharmaceutical composition of the present invention may optionally include a dissolution aid, water-soluble or water-insoluble excipient that has been conventionally used for preparing oral medicine in the art.

Referring to the preparation method of the pharmaceutical composition according to the present invention in detail.

First, glyceryl monostearate, the main shielding material, is heated to about 58 to 60 ° C. to be melted, a dissolution aid is added, and then hydrocortisone is added to dissolve and then cooled and solidified to conceal bitter taste. Glyceryl monostearate used as the main shielding material of the present invention has a melting point of 56 to 58 ° C., and melts when heated to 58 to 60 ° C., and when hydrocortisone is added thereto to dissolve it, Glyceryl monostearate is adsorbed. As the main shielding material, glyceryl monostearate is preferably used in the range of 0.1 to 2.0 parts by weight with respect to 1 part by weight of hydrocortisone. If the content is less than 0.1 part by weight, hydrocortisone cannot be adsorbed effectively and thus the shielding effect is reduced. If less than 2.0 parts by weight, the adverse effect of inhibiting the dissolution rate of hydrocortisone and it is impossible to apply to the actual manufacturing process. As described above, hydrocortisone is adsorbed on glyceryl monostearate to reduce the surface area of hydrocortisone, thereby masking the bitter taste felt when powdered hydrocortisone tablets are taken. That is, since glyceryl monostearate has a melting point of 56 to 58 ° C, it is returned to its original crystalline state when adsorbed to hydrocortisone and left at room temperature (cooled), so when it is powdered, it is maintained at 37 to 38 ° C body temperature. Hydrocortisone and glyceryl monostearate remain adsorbed on the tongue in the mouth, thereby masking the bitter taste peculiar to hydrocortisone. In addition, hydrocortisone is stable in the solid state but contains water, or in the liquid state, it is prone to oxidation reaction in the dihydroxyacetone side chain of its own, which leads to the decomposition of glyceryl monostearate. When adsorbed, the effect of preservation and stability of the formulation can be expected, and when glyceryl monostearate is used in combination with a dissolution aid such as polyoxyethylene laurate, another effect of increasing the dissolution rate of hydrocortisone can be expected.

In order to facilitate the adsorption of hydrocortisone and glyceryl monostearate, it is preferable to use 0.01 to 0.5 parts by weight of a dissolution aid for aiding the dissolution of hydrocortisone with respect to 1 part by weight of hydrocortisone. If the amount of the dissolving aid is less than 0.01 part by weight, the dissolution of hydrocortisone is lowered and there is a problem in drug efficacy. If the amount is more than 0.5 parts by weight, the dissolution of the hydrocortisone is excessive and there is a problem in the sustainability of the drug. The dissolution aid may be used at least one selected from polyoxyethylene laurate, polyoxyethylene palmitate, polyoxyethylene stearate, and polyoxyethylene oleate. These dissolution aids may be used for the purpose of meeting the 'Horcortisone' dissolution test criteria of the US Pharmacopoeia.

In addition, in the present invention, in order to remove the residual bitterness of the solidified hydrocortisone whose bitterness is masked by adsorption of glyceryl monostearate, the solidified hydrocortisone is powdered, and a sweetener is mixed therein to prevent the bitterness of the hydrogel. Obtain a cortisone oral pharmaceutical composition. The sweetener is used to mask the residual bitterness of the hydrocortisone masked by glyceryl monostearate, preferably 0.05 to 1.0 parts by weight based on 1 part by weight of hydrocortisone. If the content is less than 0.05 parts by weight, there is a problem that the remaining bitter taste is not sufficiently removed, if more than 1.0 parts by weight there is a problem that the bitterness is left behind due to the strong sweetness of the sweetener. Such sweeteners include sucralose, aspartame, acesulfame K, or stevioside, and are preferably calorie-free, having 600 times the sweetness of sugar, and physical and chemical and sensory properties such as stability, flavor profile, and solubility. It is recommended to use sucralose that is superior in properties to other sweeteners.

In addition, in the process of mixing the sweetener, by adding a water-soluble or water-insoluble excipient with the sweetener can effectively obtain the effect of improving the dissolution of hydrocortisone while effectively shielding the bitter taste of hydrocortisone. The water-soluble or water-insoluble excipient is preferably used in an amount of 0.1 to 10 parts by weight based on 1 part by weight of hydrocortisone, and if the amount is less than 0.1 part by weight or more than 10 parts by weight, there is a problem in the manufacturing process. These water-soluble or water-insoluble excipients are at least one selected from microcrystalline cellulose, hydroxypropylmethylcellulose, lactose, corn starch, pregelatinized starch, sodium starch glycolate, povidone, calcium carboxycellulose, magnesium stearate and talc which are commonly used. It may be used, and the powder, granules, capsules, tablets, dry syrup, etc. can be selected according to the formulation required.

As described above, the composition according to the present invention can effectively mask the unpleasant taste of the drug, so that even if suspended in the liquid solution is maintained because the shielding system has the advantage that there is no restriction in adaptation to the liquid agent as well as adjust the dissolution rate bioavailability Height has another advantage.

On the other hand, the pharmaceutical composition of the present invention can be finally formulated as a preparation for oral administration of powders, granules, capsules, suspension tablets, effervescent tablets or dry syrup according to conventional methods.

Preferred dosages of the compositions of the present invention vary depending on the condition and weight of the subject, the extent of the disease, the form of the composition, the route of administration and the duration of administration, but in the case of a general adult 10 to 120 mg is preferred per day, especially on a day It is preferable to divide and take 1-4 times.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.

Examples 1-2 and Comparative Examples 1-3

To the hydrocortisone oral pharmaceutical composition was prepared in the components and contents shown in Table 1.

First, the glyceryl monostearate was weighed and then completely melted while maintaining at 60 ° C., and then completely dissolved by adding 1 g of polyoxyethylene laurate and a hydrocortisone as a dissolution aid. After cooling to room temperature and solidified, the resultant was pulverized to 850 to 1000 µm using a grinder, followed by excipient (43 g of microcrystalline cellulose, lactose [40 g (Comparative Example 1), 15.5 g (Comparative Example 2), 40.5 g ( Comparative Example 3), 30.5 g (Example 1), 20.5 g (Example 2)], 2 g of carboxymethyl cellulose calcium, 2.5 g of magnesium stearate) and a sweetening agent (sucralose) were mixed to provide a powdery taste masking agent. The composition was prepared.

Glyceryl Monostearate (g) Sucralose (g) Hydrocortisone (g) Comparative Example 1 0.5 One 10 Comparative Example 2 25 Comparative Example 3 0 Example 1 10 Example 2 20 Control 0 0

Experimental Example 1

For the taste masking pharmaceutical composition prepared in Examples 1 to 2 and Comparative Examples 1 to 3 was carried out a sensory experiment to evaluate the taste in 13 adults, the results are shown in Table 2 below. The control group was made of hydrocortisone raw material without masking taste, and the bitterness of the control group (hydrocortisone raw material) was 0, and the degree of taste masking was improved +1 slightly, +2 improved, +3 very bitter, +4 bitter taste It is shown that there is almost no.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Control evaluation +1 +4 +1 +4 +4 0

As shown in Table 2, it was confirmed that the pharmaceutical composition of the embodiment according to the present invention effectively masked the bitter taste peculiar to hydrocortisone.

Experimental Example 2

Specific gravity was measured to confirm that the surface area of hydrocortisone was reduced by adsorbing hydrocortisone with glyceryl monostearate, and the results are shown in Table 3 below.

Prescription Specific gravity Control group (hydrocortisone) 0.28 to 0.32 g / cm ³ Example 1 0.73 to 0.81 g / cm ³

As shown in Table 3, in the hydrocortisone having the same weight (10 g), the specific gravity of the adsorbed to the glyceryl monostearate of Example 1 of the present invention is greater than the specific gravity of the hydrocortisone raw material. It was found that the surface area of hydrocortisone was reduced.

Experimental Example 3

The particle size distribution of the hydrocortisone raw material (control) and the bitterness masked pharmaceutical composition of Example 1 was measured, and the results are shown in Table 4 below.

Rate through the sieve Sieve number Control group (hydrocortisone) Example 1 20 (850㎛) 100% 95% 35 (500㎛) 100% 5% 50 (300㎛) 100% 0%

As shown in Table 4, the hydrocortisone raw material itself passed through all the sieves, but most of the adsorbed to the glyceryl monostearate of Example 1 of the present invention was passed only through No. 20 sieve. In other words, as the hydrocortisone raw material was adsorbed to glyceryl monostearate as a shielding material, the total particle size was increased due to the adsorbed portion while reducing the surface area of the hydrocortisone itself.

Examples 3-4 and Comparative Examples 4-6

To the hydrocortisone oral pharmaceutical composition was prepared in the ingredients and contents shown in Table 5.

First, the glyceryl monostearate was weighed and then completely melted while maintaining at 60 ° C., and then completely dissolved by adding 1 g of polyoxyethylene laurate and a hydrocortisone as a dissolution aid. Then, after cooling to room temperature and solidified, it was pulverized to 850 to 1000 µm using a grinder, and then excipient (43 g of microcrystalline cellulose, lactose [31.2 g (Comparative Example 4), 19.5 g (Comparative Example 5), 31.5 g (comparative) Example 6), 30.5 g (Example 3), 29.5 g (Example 4)], 2 g of calcium carboxycellulose cellulose, 2.5 g of magnesium stearate, and a sweetening agent (sucralose) were mixed to prepare a powdery taste masking pharmaceutical composition. Prepared.

Glyceryl Monostearate (g) Sucralose (g) Hydrocortisone (g) Comparative Example 4 10 0.3 10 Comparative Example 5 12 Comparative Example 6 0 Example 3 One Example 4 2 Control 0 0

Experimental Example 4

For the taste masking pharmaceutical composition prepared in Examples 3 to 4 and Comparative Examples 4 to 6 was carried out a sensory experiment to evaluate the taste in 13 adults, the results are shown in Table 6 below. The control group was made of hydrocortisone raw material without masking taste, and the bitterness of the control group (hydrocortisone raw material) was 0, and the degree of taste masking was improved +1 slightly, +2 improved, +3 very bitter, +4 bitter taste It is shown that there is almost no.

Comparative Example 4 Comparative Example 5 Comparative Example 6 Example 3 Example 4 Control evaluation +2 +1 +2 +4 +4 0

As shown in Table 6, it was confirmed that the pharmaceutical composition of the embodiment according to the present invention effectively masked the bitter taste peculiar to hydrocortisone.

Comparative Example 7

A powdery taste masking pharmaceutical composition was prepared by the same ingredients, contents and methods as in Example 4, except that the dissolution aid was not added in Example 4.

Experimental Example 5

The dissolution test of hydrocortisone was performed about the taste masking pharmaceutical compositions of Examples 1-4 and Comparative Example 7. Experimental method was used paddle method according to the dissolution test clause in the US Pharmacopoeia hydrocortisone tablets, the sample was hydrocortisone using a 10 mg equivalent amount of pharmaceutical composition, the eluator operating conditions 50 revolutions per minute, eluent 900 ml of silver water, the temperature was 37 ℃. The eluate was taken up to 30 minutes after the start of the elution, and the amount of the elution was analyzed by ultraviolet absorption. The results are shown in Table 7 below.

Prescription Dissolution rate (%), 30 minutes Control group (hydrocortisone) 98.0 ± 2.7 Example 1 93.2 ± 1.8 Example 2 90.0 ± 3.1 Example 3 93.8 ± 1.1 Example 4 93.5 ± 2.9 Comparative Example 7 39.8 ± 3.0

As shown in Table 7, the dissolution rate criteria of the hydrocortisone tablet is a pharmaceutical composition that masks the bitter taste of the hydrocortisone according to the present invention in the above results at 70% or more at 30 minutes in accordance with the US Pharmacopoeia hydrocortisone dissolution test term In Examples 1 to 4, it was confirmed that the dissolution rate reduction phenomenon did not appear significantly and did not affect the efficacy of hydrocortisone. However, in Comparative Example 7 without the addition of a dissolution aid, it was confirmed that the dissolution rate of the hydrocortisone was greatly decreased.

Formulation Example 1 Preparation of Syrup

The syrup was prepared by the following conventional method using the composition ratio of the pharmaceutical composition of Example 1.

A solution consisting of 0.2 g of hydrocortisone, 0.5 g of collidon, 0.04 g of carboxymethyl cellulose calcium, 0.2 g of glyceryl monostearic acid, 0.02 g of polyoxyethylene laurate, 0.02 g of sucralose, ethylenediaminetetraacetic acid, a preservative, and purified water Prepared and mixed. Water was added to this mixture to 100 ml.

Experimental Example 6

The syrup agent prepared according to Formulation Example 1 was subjected to sensory experiments to evaluate the taste of 13 children. As a result, it was confirmed that the syrup agent effectively masked the bitter taste peculiar to hydrocortisone.

As described above, the pharmaceutical composition according to the present invention can effectively shield the bitter taste of hydrocortisone by physical adsorption, and even when suspended, the shielding system is maintained, and thus there is no restriction in the application to the liquid agent.

Claims (8)

A bitter taste masking hydrocortisone oral pharmaceutical composition comprising 1 part by weight of hydrocortisone, 0.1 to 2.0 parts by weight of glyceryl monostearate as a main shielding material, and 0.05 to 1.0 parts by weight of sweetener as an auxiliary shielding material. According to claim 1, wherein the sweetener is bitter taste masked hydrocortisone oral pharmaceutical composition, characterized in that selected from sucralose, aspartame, acesulfame K and steviosides. The method of claim 1, wherein the composition is 0.01 to 0.5 parts by weight of at least one selected from polyoxy ethylene laurate, polyoxy ethylene palmitate, polyoxy ethylene stearate, and polyoxy ethylene oleate as a dissolution aid. Hydrocortisone oral pharmaceutical composition in which bitterness is masked. 2. The composition of claim 1, wherein the composition is a water-soluble or non-aqueous excipient in microcrystalline cellulose, hydroxypropylmethylcellulose, lactose, corn starch, pregelatinized starch, sodium starch glycolate, povidone, calcium carboxycellulose, magnesium stearate and talc. Bitter taste masked hydrocortisone oral pharmaceutical composition, characterized in that at least one selected from 0.1 to 10 parts by weight. The method of claim 1, wherein the pharmaceutical composition is a bitter masked hydrocortisone oral pharmaceutical composition, characterized in that the formulation is formulated as a powder, granules, capsules, suspension tablets, effervescent tablets or dry syrup. Glyceryl monostearate is melted at a temperature of 58-60 ° C., hydrocortisone is added to dissolve it, the hydrocortisone is adsorbed to glyceryl monostearate, cooled to solidify and then powdered, and sweetener is added thereto. Method for producing a hydrocortisone oral pharmaceutical composition masked bitterness characterized in that the mixing. 7. The bitterness according to claim 6, wherein the glyceryl monostearate melt is selected from polyoxyethylene laurate, polyoxy ethylene palmitate, polyoxy ethylene stearate and polyoxy ethylene oleate as a dissolution aid. A method for producing the masked hydrocortisone oral pharmaceutical composition. The method according to claim 6, wherein the glyceryl monostearate melt is a microcrystalline cellulose, hydroxypropylmethylcellulose, lactose, corn starch, pregelatinized starch, sodium starch glycolate, povidone, calcium carboxymethylcellulose, A method for preparing a bitter taste masked hydrocortisone oral pharmaceutical composition, characterized in that the addition of magnesium stearate and talc is added.